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  • 1.
    Arasu, Uma Thanigai
    et al.
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Kärnä, Riikka
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Härkönen, Kai
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Oikari, Sanna
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Koistinen, Arto
    SIB Labs, University of Eastern Finland, Kuopio, Finland.
    Kröger, Heikki
    Department of Orthopaedics and Traumatology, Kuopio University Hospital, Kuopio, Finland; Bone and Cartilage Research Unit, Surgery, Institute of Clinical Medicine, University of Eastern, Finland.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, PR China.
    Rilla, Kirsi
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles2017In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 64, 54-68 p.Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs) secreted by stem cells are potential factors mediating tissue regeneration. They travel from bone marrow stem cells into damaged tissues, suggesting that they can repair tissue injuries without directly replacing parenchymal cells. We have discovered that hyaluronan (HA) synthesis is associated with the shedding of HA-coated EVs. The aim of this study was to test whether bone marrow-derived hMSCs secrete HA-coated EVs. The EVs secreted by MSCs were isolated by differential centrifugation and characterized by nanoparticle tracking analysis. Their morphology and budding mechanisms were inspected by confocal microscopy and correlative light and electron microscopy. Hyaluronan synthesis of hMSCs was induced by lipopolysaccharide and inhibited by RNA interference and 4-methylumbelliferone. It was found that the MSCs have extremely long apical and lateral HA-coated filopodia, typical for cells with an active HA secretion. Additionally, they secreted HA-coated EVs carrying mRNAs for CD44 and all HAS isoforms. The results show that stem cells have a strong intrinsic potential for HA synthesis and EV secretion, and the amount of HA carried on EVs reflects the HA content of the original cells. These results show that the secretion of HA-coated EVs by hMSCs is a general process, that may contribute to many of the mechanisms of HA-mediated tissue regeneration. Additionally, an HA coat on EVs may regulate their interactions with target cells and participate in extracellular matrix remodeling.

  • 2.
    Arokoski, Jari
    et al.
    Department of Rehabilitation, Kuopio University Hospital, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyttinen, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Keski-Suomi Central Hospital, Jyväskylä, Finland.
    Parkkinen, Jyrki
    Laboratory Center, Pathology, Tampere University Hospital, Tampere, Finland.
    Jurvelin, Jukka
    Department of Clinical Physiology and Isotope Medicine, Kuopio University Hospital, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Nivelrikon etiopatogeneesi [Etiopathogenesis of osteoarthritis].2001In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 117, no 16, 1617-1626 p., 12182099Article in journal (Refereed)
    Abstract [fi]

    Nivelrikon patofysiologia tunnetaan huonosti. Nykykäsityksen mukaan artroosissa ei olekyse nivelruston passiivisesta kulumisesta vaan biokemiallisesta tapahtumasarjasta, jossasoluväliaineen tuhoutuminen saa ylivallan rustoa korjaavista prosesseista. Nivelrikon alkuvaiheessarustosoluissa eli kondrosyyteissä aktivoituvat sekä ruston aineosien synteesitoimintaettä rustoa hajottavien entsyymien ilmentyminen ja niitä koodaavien geenientoiminta. Nivelrikko on koko nivelen sairaus, joka aiheuttaa muutoksia niin nivelrustossa,luussa kuin pehmytosissakin. Vallitsevan käsityksen mukaan nivelrikko käynnistyynivelruston pinnallisesta vyöhykkeestä. On myös esitetty, että nivelalueen altistuminenliialliselle kuormitukselle aiheuttaisi ensin rustonalaisen luun paksunemisen ja jäykkenemisen,mikä puolestaan altistaisi nivelruston suuremmille kuormittaville voimille. Riskitekijöistätärkeimpiä ovat ikääntyminen, liikapaino, niveleen kohdistuvat vammat ja ruumiillisentyön aiheuttama liikarasitus. Perinnöllisten tekijöiden osuus on myös merkittävä.Ruston kollageenien rakennevirheiden tiedetään altistavan nivelrikolle.

  • 3.
    Arokoski, Jari
    et al.
    Kuopio University Hospital, Department of surgery and Clinic of rehabilitation, Kuopio, Finland.
    Vuoltenaho, Katriina
    Department of Medicine, Pharmacology, University of Tampere, Tampere, Finland; Tampere University Hospital, Tampere, Finland.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Kuopio, Finland.
    Moilanern, Eeva
    Department of Medicine, Pharmacology, University of Tampere, Tampere, Finland; Tampere University Hospital, Tampere, Finland.
    Nivelrikon lääkehoito [Medical treatment of osteoarthritis]2008In: Duodecim, ISSN 0012-7183, Vol. 124, 1899--1907 p.Article, review/survey (Refereed)
    Abstract [fi]

    teho ei riitä, siirrytään tulehduskipulääkkeisiin niiden haitat huomioiden. Ellei parasetamolilla ja tulehduskipulääkkeillä saada riittävää tehoa nivelrikkokipuun tai niitä ei haittavaikutusten vuoksi ole mahdollista käyttää, kipua voidaan hoitaa opioideilla. Niveleen annettu glukokortikoidi- tai hyaluronaattihoito näyttää lievittävän nivelkipua. Glukosamiini saattaa helpottaa nivelrikon oireita, mutta luotettava tieteellinen näyttö sen tehosta puuttuu edelleen. Kehitteillä on nykyisiin vaikutusmekanismeihin tukeutuvia oireita lievittäviä lääkeaineita, mutta merkittävämpi ja haastavampi pitkän aikavälin tavoite on kehittää rustovaurioita hidastavia lääkkeitä. Potentiaalisia tautiprosessiin vaikuttavia lääkeaineita ovat mm. rustomatriksia hajottavien entsyymien estäjät, typpioksidisynteesin estäjät, sytokiinimodulaattorit ja PPAR-agonistit.

  • 4.
    Beier, Frank
    et al.
    Institute for Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Eerola, Iiro
    Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
    Vuorio, Eero
    Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
    Luvalle, Phyllis
    Department of Medical Biochemistry, University of Calgary, Calgary, Alberta, Canada.
    Reichenberger, Ernest
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
    Bertling, Wolf
    Institute for Genetics, University of Bayreuth, Bayreuth, Germany.
    von der Mark, Klaus
    Institute for Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Mikko
    Variability in the upstream promoter and intron sequences of the human, mouse and chick type X collagen genes.1996In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 15, no 6, 415-422 p., 9049979Article in journal (Refereed)
    Abstract [en]

    The type X collagen gene is specifically expressed in hypertrophic chondrocytes during endochondral ossification. Transcription of the type X collagen gene by these differentiated cells is turned on at the same time as transcription of several other cartilage specific genes is switched off and before mineralization of the matrix begins. Analysis of type X collagen promoters for regulatory regions in different cell culture systems and in transgenic mice has given contradictory results suggesting major differences among species. To approach this problem, we have determined the nucleotide sequences of the two introns and upstream promoter sequences of the human and mouse type X collagen genes and compared them with those of bovine and chick. Within the promoter regions, we found three boxes of homology which are nearly continuous in the human gene but have interruptions in the murine gene. One of these interruptions was identified as a complex 1.9 kb repetitive element with homology to LINE, B1, B2 and long terminal repeat sequences. Regulatory elements of the human type X collagen gene are located upstream of the region where the repetitive element is inserted in the mouse gene, making it likely that the repetitive element is inserted between the coding region and regulatory sequences of the murine gene without interfering with its expression pattern. We also compared the sequences of the introns of both genes and found strong conservation. Comparisons of the mammalian sequences with promoter and first intron sequences of the chicken type X collagen gene revealed that only the proximal 120 nucleotides of the promoter were conserved, whereas all other sequences displayed no obvious homology to the murine and human sequences.

  • 5.
    Beier, Frank
    et al.
    Institute Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Mikko
    Institute Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Bertling, Wolf
    Institute for Genetics, University of Bayreuth, Bayreuth, Germany.
    von der Mark, Klaus
    Institute Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Transcriptional regulation of the human type X collagen gene expression.1996In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 785, 209-211 p., 8702131Article in journal (Refereed)
  • 6.
    Beier, Frank
    et al.
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Medical Biochemistry, University of Calgary, Calgary, Canada.
    Vornehm, Silvia
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    Pöschl, Ernst
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    von der Mark, Klaus
    Institut für Experimentelle Medizin, Universität Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Localization of silencer and enhancer elements in the human type X collagen gene.1997In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 66, no 2, 210-218 p., 9213222Article in journal (Refereed)
    Abstract [en]

    Collagen type X is a short, network-forming collagen expressed temporally and spatially tightly controlled in hypertrophic chondrocytes during endochondral ossification. Studies on chicken chondrocytes indicate that the regulation of type X collagen gene expression is regulated at the transcriptional level. In this study, we have analyzed the regulatory elements of the human type X collagen (Col10a1) by reporter gene constructs and transient transfections in chondrogenic and nonchondrogenic cells. Four different promoter fragments covering up to 2,864 bp of 5'-flanking sequences, either including or lacking the first intron, were linked to luciferase reporter gene and transfected into 3T3 fibroblasts, HT1080 fibrosarcoma cells, prehypertrophic chondrocytes from the resting zone, hypertrophic chondrocytes, and chondrogenic cell lines. The results indicated the presence of three regulatory elements in the human Col10a1 gene besides the proximal promoter. First, a negative regulatory element located between 2.4 and 2.8 kb upstream of the transcription initiation site was active in all nonchondrogenic cells and in prehypertrophic chondrocytes. Second, a positive, but also non-tissue-specific positive regulatory element was present in the first intron. Third, a cell-type-specific enhancer element active only in hypertrophic chondrocytes was located between -2.4 and -0.9 kb confirming a previous report by Thomas et al. [(1995): Gene 160:291-296]. The enhancing effect, however, was observed only when calcium phosphate was either used for transfection or included in the culture medium after lipofection. These findings demonstrate that the rigid control of human Col10a1 gene expression is achieved by both positive and negative regulatory elements in the gene and provide the basis for the identification of factors binding to those elements.

  • 7.
    Chang, Yanhai
    et al.
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Wang, Xiao
    Department of Galactophore, Shaanxi Provincial Cancer Hospital, Xi’an, PR China.
    Sun, Zhengming
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Jin, Zhankui
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Chen, Ming
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Wang, Xiaoqing
    Department of Orthopaedics, The Third Affiliated Hospital (Shaanxi Provincial People's Hospital), Health Science Center of Xi’an Jiaotong University, Xi’an, PR China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Guo, Xiong
    School of Public Health, Xi’an Jiaotong University Health Science Center, Key Laboratory of Trace Elements and Endemic Diseases, Ministry of Health, Xi’an, China.
    Inflammatory cytokine of IL-1β is involved in T-2 toxin-triggered chondrocyte injury and metabolism imbalance by the activation of Wnt/β-catenin signaling.2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 91, 195-201 p., 28963928Article in journal (Refereed)
    Abstract [en]

    Mycotoxin T-2 exerts a causative role in Kashin-Beck disease (KBD) suffering chondrocyte apoptosis and cartilage matrix homeostasis disruption. Recent research corroborated the aberrant levels of pro-inflammatory cytokine IL-1ß in KBD patients and mycotoxin environment. In the present study, we investigated the relevance of IL-1ß in T-2 toxin-evoked chondrocyte cytotoxic injury and aberrant catabolism. High levels of IL-1ß were detected in serum and cartilages from KBD patients and in T-2-stimulated chondrocytes. Moreover, knockdown of IL-1ß antagonized the adverse effects of T-2 on cytotoxic injury by enhancing cell viability and inhibiting apoptosis. However, exogenous supplementation of IL-1β further aggravated cell damage in response to T-2. Additionally, cessation of IL-1β rescued T-2-elicited tilt of matrix homeostasis toward catabolism by elevating the transcription of collagen II and aggrecan, promoting release of sulphated glycosaminoglycans (sGAG) and TIMP1, and suppressing matrix metalloproteinases production including MMP-1, MMP-3 and MMP-13. Conversely, IL-1β stimulation deteriorated T-2-induced disruption of matrix metabolism balance toward catabolism. Mechanistic analysis found the high activation of Wnt/β-catenin in KBD patients and chondrocytes upon T-2. Furthermore, this activation was mitigated after IL-1β inhibition, but further enhanced following IL-1β precondition. Importantly, blocking this pathway by transfection with β-catenin alleviated the adverse roles of IL-1β on cytotoxic injury and metabolism disorders under T-2 conditioning. Together, this study elucidates a new insight into how T-2 deteriorates the pathological progression of KBD by regulating inflammation-related pathways, indicating a promising anti-inflammation strategy for KBD therapy.

  • 8.
    Duan, Chen
    et al.
    Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Guo, Xiong
    Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Zhang, Xiao-Dong
    First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Yu, Han-Jie
    Northwest University, Xi'an, Shaanxi, China.
    Yan, Hua
    Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Gao, Ying
    Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Ma, Wei-Juan
    Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Gao, Zong-Qiang
    Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Xu, Peng
    Xi'an Red Cross Hospital, Xi'an, Shaanxi, China.
    Lammi, Mikko
    University of Kuopio, Kuopio, Finland.
    Comparative analysis of gene expression profiles between primary knee osteoarthritis and an osteoarthritis endemic to Northwestern China, Kashin-Beck disease.2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 3, 771-780 p., 20131229Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the differences in gene expression profiles of adult articular cartilage from patients with Kashin-Beck disease (KBD) versus those with primary knee osteoarthritis (OA).

    METHODS: The messenger RNA expression profiles of articular cartilage from patients with KBD, diagnosed according to the clinical criteria for KBD in China, were compared with those of cartilage from patients with OA, diagnosed according to the Western Ontario and McMaster Universities OA Index. Total RNA was isolated separately from 4 pairs of the KBD and OA cartilage samples, and the expression profiles were evaluated by Agilent 4x44k Whole Human Genome density oligonucleotide microarray analysis. The microarray data for selected transcripts were confirmed by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) amplification.

    RESULTS: For 1.2 x 10(4) transcripts, corresponding to 58.4% of the expressed transcripts, 2-fold changes in differential expression were revealed. Expression levels higher in KBD than in OA samples were observed in a mean + or - SD 6,439 + or - 1,041 (14.6 + or - 2.4%) of the transcripts, and expression levels were lower in KBD than in OA samples in 6,147 + or - 1,222 (14.2 + or - 2.8%) of the transcripts. After application of the selection criteria, 1.85% of the differentially expressed genes (P < 0.001 between groups) were detected. These included 233 genes, of which 195 (0.4%) were expressed at higher levels and 38 (0.08%) were expressed at lower levels in KBD than in OA cartilage. Comparisons of the quantitative RT-PCR data supported the validity of our microarray data.

    CONCLUSION: Differences between KBD and OA cartilage exhibited a similar pattern among all 4 of the pairs examined, indicating the presence of disease mechanisms, mainly chondrocyte matrix metabolism, cartilage degeneration, and apoptosis induction pathways, which contribute to cartilage destruction in KBD.

  • 9.
    Eerola, Iiro
    et al.
    Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
    Salminen, Heli
    Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
    Lammi, Pirkko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    von der Mark, Klaus
    Institute of Experimental Medicine, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
    Vuorio, Eero
    Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
    Säämänen, Anna-Marja
    Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland.
    Type X collagen, a natural component of mouse articular cartilage: association with growth, aging, and osteoarthritis.1998In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 41, no 7, 1287-1295 p., 9663487Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To perform a systematic study on the production and deposition of type X collagen in developing, aging, and osteoarthritic (OA) mouse articular cartilage.

    METHODS: Immunohistochemistry was employed to define the distribution of type X collagen and Northern analyses to determine the messenger RNA levels as an indicator of the synthetic activity of the protein.

    RESULTS: Type X collagen was observed in the epiphyseal and articular cartilage of mouse knee joints throughout development and growth. Type X collagen deposition in the transitional zone of articular cartilage became evident toward cessation of growth, at the age of 2-3 months. The most intense staining for type X collagen was limited to the tidemark, the border between uncalcified and calcified cartilage. Northern analysis confirmed that the type X collagen gene is also transcribed by articular cartilage chondrocytes. Intense immunostaining was observed in the areas of OA lesions, specifically, at sites of osteophyte formation and surface fibrillation. Type X collagen deposition was also seen in degenerating menisci.

    CONCLUSION: This study demonstrates that type X collagen is a natural component of mouse articular cartilage throughout development, growth, and aging. This finding and the deposition of type X collagen at sites of OA lesions suggest that type X collagen may have a role in providing structural support for articular cartilage.

  • 10.
    Elo, Mika
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kaarniranta, Kai
    Department of Opthalmology, Kuopio University Hospital, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hsp90 inhibitor geldanamycin increases hsp70 mRNA stabilisation but fails to activate HSF1 in cells exposed to hydrostatic pressure.2005In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1743, no 1-2, 115-119 p., 15777846Article in journal (Refereed)
    Abstract [en]

    High hydrostatic pressure (HP) increases Hsp70 protein and mRNA levels by increasing the mRNA half-life without activation of HSF1 transcription factor. We investigated whether this change in gene expression requires Hsp90, previously shown to regulate hsp70 genes via HSF1. In HeLa cells, both HP and Hsp90 inhibitor geldanamycin (GA) up-regulated Hsp70 expression through mRNA stabilisation. GA, unlike HP, increased HSF1 activation. However, when exposures were used together a marked Hsp70 response was observed with mRNA stabilisation without coincidence of HSF1 activation. Our data suggests that Hsp90 is involved in hsp70 mRNA stabilisation and the HSF1 activation can be suppressed by high HP.

  • 11.
    Elo, Mika
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Valmu, Leena
    Institute of Biotechnololgy, Biocenter Viikki, University of Helsinki, Helsinki, Finland.
    Redpath, Nicholas
    Celltech R & D, Slough, United Kingdom.
    Browne, Gareth
    Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
    Kalkkinen, Nisse
    Institute of Biotechnololgy, Biocenter Viikki, University of Helsinki, Helsinki, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    High hydrostatic pressure inhibits the biosynthesis of eukaryotic elongation factor-2.2005In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 94, no 3, 497-507 p., 15534876Article in journal (Refereed)
    Abstract [en]

    High continuous hydrostatic pressure is known to inhibit the total cellular protein synthesis. In this study, our goal was to identify pressure-regulated proteins by using two dimensional gel electrophoresis and mass spectrometry. This analysis showed that under 30 MPa continuous hydrostatic pressure the biosynthesis of eukaryotic elongation factor-2 (eEF-2) was inhibited both in HeLa carcinoma and T/C28a4 chondrocytic cell lines. Western blot analysis of HeLa cells revealed that the cellular protein level of eEF-2 decreased by 40%-50% within 12 h of the pressure treatment. However, the steady-state mRNA level of eEF-2 was not affected by the pressure. Cycloheximide addition after 4 h-pressure treatment suggested that the half-life of eEF-2 protein was shorter in pressurized cells. eEF-2 is responsible for the translocation of ribosome along the specific mRNA during translation, and its phosphorylation prevents the ribosomal translocation. Therefore, increased phosphorylation of eEF-2 was considered as one mechanism that could explain the reduced level of protein synthesis in pressurized HeLa cell cultures. However, Western blot analysis with an antibody recognizing the Thr56-phosphorylated form of eEF-2 showed that phosphorylation of eEF-2 was not elevated in pressurized samples. In conclusion, the inhibition of protein synthesis under high pressure occurs independent of the phosphorylation of eEF-2. However, this inhibition may result from the decrease of cellular eEF-2 protein.

  • 12.
    Elo, Mika
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kaarniranta, Kai
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Auriola, Seppo
    Department of Pharmaceutical Chemistry, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Differential regulation of stress proteins by high hydrostatic pressure, heat shock, and unbalanced calcium homeostasis in chondrocytic cells.2000In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 79, no 4, 610-619 p., 10996852Article in journal (Refereed)
    Abstract [en]

    High hydrostatic pressure (HP) has recently been shown to increase cellular heat shock protein 70 (Hsp70) level in a specific way that does not involve transcriptional activation of the gene, but rather the stabilisation of the mRNA for Hsp70. In this study, we investigated whether there are other observable changes caused by HP stress, and compared them with those induced by certain other forms of stressors. A chondrocytic cell line T/C28a4 was exposed to 30 MPa continuous HP, heat shock at 43 degrees C, and increased cytosolic calcium concentration by the addition of sarco-endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin (25 nM) or calcium ionophore A23187 (1 microM) in the cultures. The protein synthesis was studied by in vitro metabolic labelling followed by one- and two-dimensional polyacrylamide gel electrophoresis, and mass spectrometry was utilized to confirm the identity of the protein spots on two-dimensional gels. Continuous 30 MPa HP increased remarkably the relative labelling of Hsp70. Labelling of Hsp90 was also increased by 15-20%, although no clear change was evident at the protein level in Western blots. Elevated intracellular Ca(2+) concentration induced by thapsigargin and calcium ionophore A23187 increased mainly the synthesis of glucose-regulated protein 78 (Grp78/BiP), whereas Hsp70 and Hsp90 were decreased by the treatment. Heat shock was the strongest inducer of Hsp70 and Hsp90. This study further confirmed the induction of Hsp70 in chondrocytic cells exposed to high HP, but it also showed that calcium-mediated responses are unlikely to cause the stress response observed in the hydrostatically pressurized cells.

  • 13.
    Elo, Mika
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kaarniranta, Kai
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Specific induction of heat shock protein 90beta by high hydrostatic pressure.2003In: Biorheology, ISSN 0006-355X, E-ISSN 1878-5034, Vol. 40, no 1-3, 141-146 p., 12454398Article in journal (Refereed)
    Abstract [en]

    In chondrocytes, a low-amplitude intermittent hydrostatic pressure induces production of extracellular matrix molecules, while high hydrostatic pressure inhibits it. High pressure increases cellular heat shock protein 70 level in a number of cell types on account of increased stabilisation of the heat shock protein 70 mRNA. In our experiments, only bovine primary chondrocytes, but not an immortalized chondrocytic cell line, could resist the induction of the stress response in the presence of continuous 30 MPa hydrostatic pressure. We have recently shown that protein synthesis is required for the stabilization. According to two-dimensional gel electrophoresis the synthesis of heat shock protein 90 was also increased in a chondrocytic cell line and in HeLa cells, and mass spectrometric analysis suggested that the induction was rather due to increase in heat shock protein 90beta than in heat shock protein 90alpha. The stress response was rather intense in HeLa cells, therefore, we investigated the effect of continuous 30 MPa hydrostatic pressure on the expression of the two heat shock protein 90 genes in HeLa cells using Northern and Western blot analyses. Heat shock protein 90beta mRNA level increased within 6 hours of exposure to 30 MPa hydrostatic pressure, while hsp90alpha level remained stable. At protein level there was a clear increase in the heat shock protein 90beta/heat shock protein 90alpha ratio, too. These results show a specific regulation of stress proteins in cells exposed to high hydrostatic pressure.

  • 14.
    Espanha, Maria
    et al.
    Faculty of Human Kinetics, Technical University of Lisboa, Estrada da Costa, Cruz Quehrada, Lishoa, Portugal.
    Lammi, Pirkko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyttinen, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Extracellular matrix composition of full-thickness defect repair tissue is little influenced by exercise in rat articular cartilage.2001In: Connective Tissue Research, ISSN 0300-8207, E-ISSN 1607-8438, Vol. 42, no 2, 97-109 p., 11718471Article in journal (Refereed)
    Abstract [en]

    Full-thickness articular cartilage defects in the femoral condyles of adult rats were examined four and eight weeks after injury. Quantitative polarized light microscopic analysis showed that birefringence of the tissue in the central repair area increased more in rats exercised on a treadmill. Glycosaminoglycan content in the repair tissue was also higher than in the intermittent active motion group at four weeks after injury, but by eight weeks the levels were similar in both groups. No normal-looking articular cartilage was formed in the lesions, and only in one animal type II collagen was observed in the superficial zone of repair tissue. No 3B3(-) antigenicity of the proteoglycans was seen during repair. In conclusion, exercise minimally modified the repair of full-thickness articular cartilage defects in adult rats. The repair in the exercised group may occur slightly faster in the early stages but no difference was seen at the eight week time interval between the exercised and the intermittently active group.

  • 15.
    Felszeghy, Szabolcs
    et al.
    Department of Anatomy, Histology and Embryology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
    Holló, Krisztina
    Department of Anatomy, Histology and Embryology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
    Módis, Laszlo
    Department of Anatomy, Histology and Embryology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Type X collagen in human enamel development: a possible role in mineralization.2000In: Acta Odontologica Scandinavica, ISSN 0001-6357, E-ISSN 1502-3850, Vol. 58, no 4, 171-176 p., 11045371Article in journal (Refereed)
    Abstract [en]

    Although type X collagen is one of the key molecules in endochondral ossification, no data are available on whether it is present in dental structures when mineralization is proceeding. We therefore monitored the appearance of type X collagen in tooth germs of human samples ranging in gestational age from 17-week-old fetuses to 9-week-old newborn. Using immunohistochemistry, ELISA techniques, and Western blotting, we show that type X collagen is present in human tooth germ during enamel maturation. Intense immunohistochemical staining for collagen type X was observed in the enamel and in the apical parts of secretory ameloblast at the bell stage when the dentine and enamel matrix were already under formation. The odontoblasts, the dentine, and the pulp were not stained. In the early (9-week) postnatal stage, the staining for collagen type X in the enamel matrix was diminished, and only a very weak signal could be detected in the secretory ameloblasts. A positive reaction for collagen type X was also observed in ELISA assay of extracts obtained from human embryonic enamel and hypertrophic cartilage samples. The Western blot analysis of the enamel demonstrated that size of the molecule detected by MoAb X53 is characteristic of the type X collagen. This correlates well with our immunohistochemical findings. Based on these data, we propose that type X collagen is one of the candidate molecules present in the enamel matrix that might be involved in mineralization of the enamel.

  • 16.
    Fick, James
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Huttu, Mari
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Korhonen, Rami
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    In vitro glycation of articular cartilage alters the biomechanical response of chondrocytes in a depth-dependent manner2014In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 22, no 10, 1410-1418 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine if increasing cartilage cross-links through in vitro glycation of cartilage explants can alter the biomechanical response of chondrocytes to compressive deformation.

    METHOD: Bovine osteochondral explants were either incubated with cell culture solution supplemented with (n = 7) or without (n = 7) ribose for 42 h in order to induce glycation. Deformation-induced changes in cell volume, dimensions and local tissue strains were determined through confocal laser scanning microscopy (CLSM) and the use of a custom built micro-compression device. Osteochondral explants were also utilized to demonstrate changes in depth-wise tissue properties, biomechanical tissue properties and cross-links such as pentosidine (Pent), hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP).

    RESULTS: The ribose treated osteochondral samples experienced reduced cell volume deformation in the upper tissue zone by ∼ 8% (P = 0.005), as compared the control samples, through restricting cell expansion. In the deeper tissue zone, cell volume deformation was increased by ∼ 12% (P < 0.001) via the transmission of mechanical signals further into the tissue depth. Biomechanical testing of the ribose treated osteochondral samples demonstrated an increase in the equilibrium and dynamic strain dependent moduli (P < 0.001 and P = 0.008, respectively). The biochemical analysis revealed an increase in Pent cross-links (P < 0.001). Depth-wise tissue property analyses revealed increased levels of carbohydrate content, greater levels of fixed charge density and an increased carbohydrate to protein ratio from 6 to 16%, 55-100% and 72-79% of the normalized tissue thickness (from the surface), respectively, in the ribose-treated group (P < 0.05).

    CONCLUSION: In vitro glycation alters the biomechanical response of chondrocytes in cartilage differently in upper and deeper zones, offering possible insights into how aging could alter cell deformation behavior in cartilage.

  • 17.
    Florea, Cristina
    et al.
    "Politehnica” University of Timisoara, Mechanical Engineering Faculty, Mechatronics Department, Timisoara, Romania; University of Eastern Finland, Department of Applied Physics, Kuopio, Finland.
    Jakorinne, Asmo
    Savonia University of Applied Sciences, School of Engineering and Technology, Kuopio, Finland.
    Lammi, Mikko
    University of Eastern Finland, Department of Biosciences, Kuopio, Finland.
    Davidescu, Arjana
    “Politehnica” University of Timisoara, Mechanical Engineering Faculty, Mechatronics Department, Timisoara, Romania.
    Korhonen, Rami
    University of Eastern Finland, Department of Applied Physics, Kuopio, Finland.
    Determination of mechanical properties of chondrocytes in articular cartilage using atomic force microscopy2014In: Solid State Phenomena, ISSN 1012-0394, E-ISSN 1662-9779, Vol. 216, 134-139 p.Article in journal (Refereed)
    Abstract [en]

    Atomic Force Microscopy (AFM) based nanoindentation is a widely used technique for measuring mechanical properties of living cells, providing information for understanding their mechanobiological behavior. However, very local properties of cell surfaces have not been characterized earlier. The goal of this study was to develop an AFM-based technique to determine local elastic properties of bovine articular chondrocytes. The Youngs modulus of chondrocytes was 19.3 ± 5.6 kPa for spread cells and 10 ± 4.1 kPa for the round cells. The results were compared to previous studies in which different techniques were used to obtain more global properties of chondrocytes. Our findings suggest that using nanosized AFM tips, the very local cell properties can be measured.

  • 18.
    Florea, Cristina
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Tanska, Petri
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Mononen, Mika
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi’an, China.
    Laasanen, Mikko
    School of Engineering and Technology, Savonia University of Applied Sciences, Kuopio, Finland.
    Korhonen, Rami
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland.
    A combined experimental atomic force microscopy-based nanoindentation and computational modeling approach to unravel the key contributors to the time-dependent mechanical behavior of single cells2017In: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940, Vol. 16, no 1, 297-311 p., 27554263Article in journal (Refereed)
    Abstract [en]

    Cellular responses to mechanical stimuli are influenced by the mechanical properties of cells and the surrounding tissue matrix. Cells exhibit viscoelastic behavior in response to an applied stress. This has been attributed to fluid flow-dependent and flow-independent mechanisms. However, the particular mechanism that controls the local time-dependent behavior of cells is unknown. Here, a combined approach of experimental AFM nanoindentation with computational modeling is proposed, taking into account complex material behavior. Three constitutive models (porohyperelastic, viscohyperelastic, poroviscohyperelastic) in tandem with optimization algorithms were employed to capture the experimental stress relaxation data of chondrocytes at 5 % strain. The poroviscohyperelastic models with and without fluid flow allowed through the cell membrane provided excellent description of the experimental time-dependent cell responses (normalized mean squared error (NMSE) of 0.003 between the model and experiments). The viscohyperelastic model without fluid could not follow the entire experimental data that well (NMSE = 0.005), while the porohyperelastic model could not capture it at all (NMSE = 0.383). We also show by parametric analysis that the fluid flow has a small, but essential effect on the loading phase and short-term cell relaxation response, while the solid viscoelasticity controls the longer-term responses. We suggest that the local time-dependent cell mechanical response is determined by the combined effects of intrinsic viscoelasticity of the cytoskeleton and fluid flow redistribution in the cells, although the contribution of fluid flow is smaller when using a nanosized probe and moderate indentation rate. The present approach provides new insights into viscoelastic responses of chondrocytes, important for further understanding cell mechanobiological mechanisms in health and disease.

  • 19.
    Guo, Xiong
    et al.
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    Aigner, Thomas
    Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Pirkko
    Institute of Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Lammi, Mikko
    Institute of Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Zhang, Ju Ren
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    Wang, Jian Ming
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    Zhang, Fu Qiang
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    von der Mark, Klaus
    Institute of Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
    Investigation of abnormal chondrocyte differentiation and differential expression of collagen types I, II, III, VI and X in articular cartilage from patients with Kashin-Beck disease1998In: Chinese Journal of Pathology, Vol. 27, 19-21 p.Article in journal (Refereed)
  • 20.
    Guo, Xiong
    et al.
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    Lammi, Mikko
    Institute of Molecular Medicine, University of Erlangen-Nurnberg, Erlangen, Germany.
    Aigner, Thomas
    Department of Pathology, University of Erlangen-Nurnberg, Erlangen, Germany.
    Lammi, Pirkko
    Institute of Molecular Medicine, University of Erlangen-Nurnberg, Erlangen, Germany.
    Vornehm, Silvia
    Institute of Molecular Medicine, University of Erlangen-Nurnberg, Erlangen, Germany.
    Yu, Zhidao
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    Xiong, Yongmin
    Institute of Endemic Diseases, Medical College of Xi'an Jiaotong University, Xi'an, China.
    von der Mark, Klaus
    Institute of Molecular Medicine, University of Erlangen-Nurnberg, Erlangen, Germany.
    Effect of low selenium on chondrocyte differentation and differential expression of collagen types I, II and X in articular cartilage from mini-pigs2000In: Journal of Xi'an Medical University, ISSN 1671-8259, Vol. 12, 108-112 p.Article in journal (Other academic)
  • 21.
    Guo, Xiong
    et al.
    Institute of Endemic Diseases, School of Public Health, Xi'an Jiaotong University, Xi'an, China.
    Ma, Wei-Juan
    Institute of Endemic Diseases, School of Public Health, Xi'an Jiaotong University, Xi'an, China.
    Zhang, Feng
    Institute of Endemic Diseases, School of Public Health, Xi'an Jiaotong University, Xi'an, China.
    Ren, Feng-Lin
    Institute of Endemic Diseases, School of Public Health, Xi'an Jiaotong University, Xi'an, China.
    Qu, Cheng-Juan
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Recent advances in the research of an endemic osteochondropathy in China: Kashin-Beck disease2014In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 22, no 11, 1774-1783 p., 25106677Article, review/survey (Refereed)
    Abstract [en]

    Kashin-Beck disease (KBD) is an endemic chronic osteochondral disease, which has a high prevalence and morbidity in the Eastern Siberia of Russia, and in the broad diagonal, northern-east to southern-west belt in China and North Korea. In 1990's, it was estimated that in China 1–3 million people had some degree of symptoms of the disease, although even higher estimates have been presented. In China, the extensive prevalence peaked in the late 1950's, but since then, in contrast to the global trend of the osteoarthritis (OA), the number of cases has been dramatically falling. Up to 2013, there are 0.64 millions patients with the KBD and 1.16 millions at risk in 377 counties of 13 provinces or autonomous regions. This is obviously thanks to the preventive efforts carried out, which include providing millions of people with dietary supplements and clean water, as well as relocation of whole villages in China. However, relatively little is known about the molecular mechanisms behind the cartilage damage, the genetic and the environmental risk factors, and the rationale of the preventive effects. During the last decade, new data on a cellular and molecular level has begun to accumulate, which hopefully will uncover the grounds of the disease.

  • 22.
    Guo, Xiong
    et al.
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Zhang, Feng
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Wang, Xi
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Wu, Cuiyan
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Ning, Yujie
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Yu, Fangfang
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Younus, Mohammad Imran
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of PR of China, Xi'an Jiaotong University, Xi'an, China .
    Yu, Jun
    Institute of Kashin-Beck Disease, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin, China.
    Liu, Hui
    Institute of Kashin-Beck Disease, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin, China.
    Cao, Yanhong
    Institute of Kashin-Beck Disease, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin, China.
    Kashin-Beck Disease (KBD)2017In: Endemic Disease in China / [ed] Dianjun Sun, Beijing: People's Medical Publishing House , 2017, 150-211 p.Chapter in book (Refereed)
  • 23.
    Haapala, Jussi
    et al.
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland; Department of Rehabilitation Clinic, Kuopio University Hospital, Kuopio, Finland.
    Arokoski, Jari
    Department of Rehabilitation Clinic, Kuopio University Hospital, Kuopio, Finland.
    Hyttinen, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kovanen, Vuokko
    Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland.
    Remobilization does not fully restore immobilization induced articular cartilage atrophy.1999In: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, no 362, 218-229 p., 10335301Article in journal (Refereed)
    Abstract [en]

    The recovery of articular cartilage from immobilization induced atrophy was studied. The right hind limbs of 29-week-old beagle dogs were immobilized for 11 weeks and then remobilized for 50 weeks. Cartilage from the immobilized knee was compared with tissue from age matched control animals. After the immobilization period, uncalcified articular cartilage glycosaminoglycan concentration was reduced by 20% to 23%, the reduction being largest (44%) in the superficial zone. The collagen fibril network showed no significant changes, but the amount of collagen crosslinks was reduced (13.5%) during immobilization. After remobilization, glycosaminoglycan concentration was restored at most sites, except for in the upper parts of uncalcified cartilage in the medial femoral and tibial condyles (9% to 17% less glycosaminoglycans than in controls). The incorporation of 35SO4 was not changed, and remobilization also did not alter the birefringence of collagen fibrils. Remobilization restored the proportion of collagen crosslinks to the control level. The changes induced by joint unloading were reversible at most sites investigated, but full restoration of articular cartilage glycosaminoglycan concentration was not obtained in all sites, even after remobilization for 50 weeks. This suggests that lengthy immobilization of a joint can cause long lasting articular cartilage proteoglycan alterations at the same time as collagen organization remains largely unchanged. Because proteoglycans exert strong influence on the biomechanical properties of cartilage, lengthy immobilization may jeopardize the well being of articular cartilage.

  • 24.
    Haapala, Jussi
    et al.
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Inkinen, Ritva
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Ågren, Ulla
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Coordinated regulation of hyaluronan and aggrecan content in the articular cartilage of immobilized and exercised dogs.1996In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 23, no 9, 1586-1593 p., 8877929Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the influence of joint loading and immobilization on articular cartilage hyaluronan concentration and histological distribution in the knee joints of young dogs subjected to 11 weeks' immobilization by splinting, and 15 weeks' running exercise at a rate of 40 km/day.

    METHODS: The amount of hyaluronan in articular cartilage was determined by a competitive binding assay using a biotinylated hyaluronan binding complex (HABC) of aggrecan and link protein. Histologic sections were stained for the localization of hyaluronan with the HABC probe. Extracted proteoglycans were characterized by sodium dodecyl sulfate agarose gel electrophoresis.

    RESULTS: Immobilization significantly reduced the concentration of hyaluronan in all sites studied (tibial and femoral condyles, patellar surface of femur). The proportion of hyaluronan to total uronic acid (mainly from aggrecan) remained unchanged because of a concurrent decrease in aggrecan. The ratio of hyaluronan and aggrecan remained constant also in runners. The staining pattern of free hyaluronan in the tissue sections and the electrophoretic mobility of the extracted proteoglycans were not affected by the different loading regimes.

    CONCLUSION: Reduced joint loading due to splint immobilization significantly decreases both hyaluronan and aggrecan in the articular cartilage. The remarkably parallel changes in aggrecan and hyaluronan content suggest that joint loading exerts a coordinated influence on their metabolism.

  • 25.
    Han, Jing
    et al.
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Guo, Xiong
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Tan, Wuhong
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Zhang, Feng
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Liu, Jiangtao
    Faculty of Public Health, College Medicine, Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi’an Jiaotong University, Xi’an, China.
    Wang, Weizhuo
    Department of Orthopedics Surgery, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China.
    Xu, Peng
    Department of Orthopaedics Surgery, The Xi’an Red Cross Hospital, Xi’an, China.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Kuopio, Finland .
    The expression of p-ATF2 involved in the chondeocytes apoptosis of an endemic osteoarthritis, Kashin-Beck disease2013In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 14, 209Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of the study was to understand the function and expression of ATF2 by JNK and p38 signal pathways in the chondrocytes apoptosis of articular cartilage of the Kashin-Beck disease (KBD).

    METHODS: The changes of ATF2, JNK and p38 mRNAs and proteins were investigated between cartilage and chondrocyte as well as KBD and normal. JNK and p38 inhibitors were used as treatments to prevent apoptosis in chondrocytes from KBD patients.

    RESULTS: It was found that the protein levels of p-p38, p-JNK, ATF2 and p-ATF2 increased in KBD human cartilage which is in line with the higher mRNA levels of p38, JNK and ATF2 as compared both with normal cartilage and KBD chondrocytes. In addition, p-ATF2 was only detected in KBD cartilage. Furthermore, JNK inhibitor was more effective than p38 inhibitor in preventing chondrocyte apoptosis at equal concentrations of 10 μM.

    CONCLUSION: These findings indicated the expression of p-ATF2 by JNK and p38 signal pathways involved in the chondrocyte apoptosis in cartilage with KBD.

  • 26.
    Han, Jing
    et al.
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China; Biomat lab, Department of Mechanical Engineering, National University of Singapore, Singapore.
    Li, Danyang
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wang, Dong
    Biomat lab, Department of Mechanical Engineering, National University of Singapore, 117576, Singapore; Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
    Wang, Liyun
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR Chin.
    Guo, Xiong
    School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR Chin.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, PR China.
    Altered expression of chondroitin sulfate structure modifying sulfotransferases in the articular cartilage from adult osteoarthritis and Kashin-Beck disease2017In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 25, no 8, 1372-1375 p., 28274888Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the expression of enzymes involved in chondroitin sulfate (CS) sulfation in the articular cartilage isolated from adult patients with osteoarthritis (OA) and Kashin-Beck disease (KBD), using normal adults as controls.

    METHODS: Articular cartilage samples were collected from normal, OA and KBD adults aged 38-60 years old, and divided into three groups with six individual subjects in each group. The morphology and pathology grading of knee joint cartilage was examined by Safranin O staining. The localization and expression of enzymes involved in CS sulfation (CHST-3, CHST-11, CHST-12, CHST-13, CHST-15, and UST) were examined by immunohistochemical staining and semi-quantitative analysis.

    RESULTS: Positive staining rates for anabolic enzymes CHST-3, CHST-12, CHST-15, and UST were lower in the KBD and OA groups than those in the control group. Meanwhile, reduced levels of CHST-11, and CHST-13 in KBD group were observed, in contrast to those in OA and control groups. The expressions of all six CS sulfation enzymes were less detected in the superficial and deep zones of KBD cartilage compared with control and OA cartilage.

    CONCLUSION: The reduced expression of the CS structure modifying sulfotransferases in the chondrocytes of both KBD and OA adult patients may provide explanations for their cartilage damages, and therapeutic targets for their treatment.

  • 27.
    Helminen, Heikki
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyttinen, Mika
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospital, Kuopio, Finland.
    Lapveteläinen, Tuomo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Jurvelin, Jukka
    Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Regular joint loading in youth assists in the establishment and strengthening of the collagen network of articular cartilage and contributes to the prevention of osteoarthrosis later in life. A hypothesis.2000In: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 18, no 5, 245-257 p., 10959613Article, review/survey (Refereed)
  • 28.
    Helminen, Heikki
    et al.
    University of Kuopio, Kuopio, Finland.
    Kiviranta, Ilkka
    University of Kuopio, Kuopio, Finland.
    Säämänen, Anna-Marja
    University of Kuopio, Kuopio, Finland.
    Jurvelin, Jukka
    University of Kuopio, Kuopio, Finland.
    Paukkonen, Kari
    University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Kuopio, Kuopio, Finland.
    Lapveteläinen, Tuomo
    Department of Kuopio, Kuopio, Finland.
    Hyttinen, Mika
    Department of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Kuopio, Kuopio, Finland.
    Superficial zone of articular cartilage after immobilization and running training: is proteoglycan depletion the clue to the pathogenesis of osteoarthrosis1993In: Wolff’s Law and Connective Tissue Regulation / [ed] Günter Regling, de Gruyter , 1993, 279-282 p.Chapter in book (Refereed)
  • 29.
    Helminen, Heikki
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Säämänen, Anna-Marja
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Jurvelin, Jukka
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kiviranta, Ilkka
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kuormituksen vaikutus nivelrustoon [The effects of loading on articular cartilage].1992In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 108, no 12, 1097-1107 p., 1366060Article, review/survey (Refereed)
    Abstract [fi]

    Nivelen kuormitus on tärkeimpiä nivelruston aineenvaihduntaan ja rakenteeseen vaikuttavia fysiologisia tekijöitä. Kohtuullinen rytminen kuormitus lisää nuoren ihmisen nivelruston proteoglykaanipitoisuutta. Tämän vaikutuksesta rusto jäykistyy ja kasvaa paksuutta. Hyvin voimakas kuormitus ei aiheuta tällaista positiivista vastetta. Toisaalta nivelkuormituksen puuttuminen pienentää ruston proteoglykaanipitoisuutta ja heikentää kimmo-ominaisuuksia. Nämä surkastumismuutokset ovat suurimmaksi osaksi–elleivät kokonaan–korjautuvia. Kohtuullisella nivelkuormituksella voidaan siis ylläpitää ja parantaa nivelruston ominaisuuksia. Pitkäaikaisen liikkumattomuuden jälkeen nivelrusto on heikompi kuin normaalisti ja voi vaurioitua niveltä voimakkaasti kuormitettaessa. Siksi nivelen kuormitusta pitää lisätä toipumisvaiheessa vähitellen.

  • 30.
    Huttu, Mari
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Turunen, Siru
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Sokolinski, Viktoria
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Tiitu, Virpi
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; SIB-Labs, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
    Korhonen, Rami K
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Effects of medium and temperature on cellular responses in the superficial zone of hypo-osmotically challenged articular cartilage.2012In: Journal of Functional Biomaterials, ISSN 2079-4983, Vol. 3, no 3, 544-555 p., 23807905Article in journal (Refereed)
    Abstract [en]

    Osmotic loading of articular cartilage has been used to study cell-tissue interactions and mechanisms in chondrocyte volume regulation in situ. Since cell volume changes are likely to affect cell's mechanotransduction, it is important to understand how environmental factors, such as composition of the immersion medium and temperature affect cell volume changes in situ in osmotically challenged articular cartilage. In this study, chondrocytes were imaged in situ with a confocal laser scanning microscope (CLSM) through cartilage surface before and 3 min and 120 min after a hypo-osmotic challenge. Samples were measured either in phosphate buffered saline (PBS, without glucose and Ca(2+)) or in Dulbecco's modified Eagle's medium (DMEM, with glucose and Ca(2+)), and at 21 °C or at 37 °C. In all groups, cell volumes increased shortly after the hypotonic challenge and then recovered back to the original volumes. At both observation time points, cell volume changes as a result of the osmotic challenge were similar in PBS and DMEM in both temperatures. Our results indicate that the initial chondrocyte swelling and volume recovery as a result of the hypo-osmotic challenge of cartilage are not dependent on commonly used immersion media or temperature.

  • 31.
    Hyttinen, Mika
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospital, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lapveteläinen, Tuomo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Mauranen, Kari
    Department of Health Policy and Management, University of Kuopio, Kuopio, Finland.
    Király, Kari
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Age matters: collagen birefringence of superficial articular cartilage is increased in young guinea-pigs but decreased in older animals after identical physiological type of joint loading.2001In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 9, no 8, 694-701 p., 11795988Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To compare responses of the collagen network and glycosaminoglycans (GAGs) of articular cartilage to physiological type of joint loading in young growing and adult mature guinea-pigs.

    DESIGN: 10- and 44-week-old guinea-pigs were accustomed to treadmill running for 3 weeks. Thereafter the animals ran 2500 m/day, 5 days a week, for 15 weeks. Articular cartilage specimens from knee joints were collected at 28 and 62 weeks. Osteoarthritis (OA) prevalence and severity was evaluated by aid of light microscopy. The degree of collagen fibril network organization and content was analyzed with quantitative polarized light microscopy. The local concentration of GAGs was determined from cartilage sections with digital densitometry after safranin-O staining.

    RESULTS: In the young guinea-pigs, running increased up to 24% the optical retardation of polarized light by collagen in the superficial articular cartilage of femur, indicating either a higher degree of fibril assembly and organization or increased amount of collagen, or both. In contrast, in the adult mature animals the optical retardation decreased almost 50% after joint loading (P< 0.01-0.001). Running did not increase cartilage fibrillation. Significant changes in GAG content of cartilage were not found either in the young or adult mature runners.

    CONCLUSIONS: Increased birefringence of the superficial articular cartilage after joint loading in young guinea-pigs can be interpreted to be a sign of improved and decreased birefringence in older animals a sign of worsened property of the collagen network. It can be suggested therefore that joint loading strengthened the collagen network in the young runners. It can be hypothesized further that with time the inferior property of the collagen network predisposes the older runners to earlier OA than in controls.

  • 32.
    Inkinen, Ritva
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Agren, Ulla
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Raija
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Puustjärvi, Kaija
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyaluronan distribution in the human and canine intervertebral disc and cartilage endplate.1999In: The Histochemical Journal, ISSN 0018-2214, E-ISSN 1573-6865, Vol. 31, no 9, 579-587 p., 10579627Article in journal (Refereed)
    Abstract [en]

    A biotinylated complex of aggrecan G1-domain and link protein was used to characterize the distribution of hyaluronan in paraffin-embedded sections of adult human and canine intervertebral disc and cartilage endplate. Limited chondroitinase ABC and trypsin digestions of the sections before staining was utilized to expose hyaluronan potentially masked by aggrecan. Hyaluronan concentration and hyaluronan to uronic acid ratio in different parts of the discs were measured as a background for the histological analysis. Hyaluronan staining was strong in the nucleus pulposus and inner parts of annulus fibrosus of both species, corroborated by biochemical assays of the same compartments. Particularly in human samples, hyaluronan in the interterritorial matrix of nucleus pulposus and annulus fibrosus was readily accessible to the probe without enzyme treatments. In contrast, the cell-associated hyaluronan signal was enhanced after trypsin or limited chondroitinase ABC-treatment of the sections, suggesting that pericellular hyaluronan was more masked by aggrecan than in the distant matrix. A puzzling feature of canine cartilage endplate cells was their intensive cell-associated hyaluronan signal, part of which appeared intracellular. Hyaluronan was abundant between the collagenous lamellae in annulus fibrosus, perhaps important in the plasticity of this tissue.

  • 33.
    Inkinen, Ritva
    et al.
    Department of Anatomy, University of Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Finland.
    Lehmonen, Sirpa
    Department of Anatomy, University of Kuopio, Finland.
    Puustjärvi, Kaija
    Department of Anatomy, University of Kuopio, Finland.
    Kääpä, Eeva
    Department of Physical Medicine and Rehabilitation,Helsinki University Hospital, Helsinki, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Finland.
    Relative increase of biglycan and decorin and altered chondroitin sulfate epitopes in the degenerating human intervertebral disc.1998In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 25, no 3, 506-514 p., 9517772Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Proteoglycans are major components of the extracellular matrix of the intervertebral disc. They are vital for the biomechanical properties of the tissue, and are subject to changes in disc degeneration. We aimed to further define these changes and their relationship to normal aging.

    METHODS: Normal discs (age 13-53 years, n = 6) were analyzed from 5 different sites across the sagittal anterior-posterior direction. Degenerated anterior annulus fibrosus was collected from 7 patients aged 39-46 years. Extracted proteoglycans were separated using agarose and polyacrylamide gel electrophoresis and detected with toluidine blue staining and Western blotting.

    RESULTS: The center of the disc showed the highest level of total proteoglycans, but lowest levels of decorin and biglycan. Western blots displayed reduced signal for both glycanated and nonglycanated biglycan and decorin after adolescence, while an increased signal of biglycan was observed in degenerated annuli. The 7D4(-) and 3B3(-) epitopes on native chondroitin sulfate chains were present in the large proteoglycans of intervertebral discs, but their signal intensity had no correlation to degeneration. Chondroitinase ABC digestion of the blots brought up 7D4(+) signal in the small proteoglycans of degenerated, but not in healthy tissue. Decrease or total loss of 2B6(+) epitope (indicating 4-sulfated stubs of chondroitin sulfate chains) were found in the large proteoglycans of all degenerated annuli.

    CONCLUSION: Human intervertebral disc degeneration involves the accumulation of decorin and biglycan relative to other uronic acid containing proteoglycans, the disappearance of 4-sulfated core region in aggrecan-like large proteoglycans, and the emergence of a core structure in the chains of small proteoglycans reacting with the 7D4 antibody; these findings indicate a fundamental alteration in matrix properties that may contribute to the pathogenesis of the disease.

  • 34.
    Inkinen, Satu
    et al.
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland.
    Liukkonen, Jukka
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Ylärinne, Janne
    School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Puhakka, Pia
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland.
    Lammi, Mikko
    School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Virén, Tuomas
    Cancer Center, Kuopio University Hospital, Kuopio, Finland.
    Jurvelin, Jukka
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Töyräs, Juha
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland; Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland.
    Collagen and chondrocyte concentrations control ultrasound scattering in agarose scaffolds2014In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 40, no 9, 2162-2171 p.Article in journal (Refereed)
    Abstract [en]

    Ultrasound imaging has been proposed for diagnostics of osteoarthritis and cartilage injuries in vivo. However, the specific contribution of chondrocytes and collagen to ultrasound scattering in articular cartilage has not been systematically studied. We investigated the role of these tissue structures by measuring ultrasound scattering in agarose scaffolds with varying collagen and chondrocyte concentrations. Ultrasound catheters with center frequencies of 9 MHz (7.1–11.0 MHz, −6 dB) and 40 MHz (30.1–45.3 MHz, −6 dB) were applied using an intravascular ultrasound device. Ultrasound backscattering quantified in a region of interest starting right below sample surface differed significantly (p < 0.05) with the concentrations of collagen and chondrocytes. An ultrasound frequency of 40 MHz, as compared with 9 MHz, was more sensitive to variations in collagen and chondrocyte concentrations. The present findings may improve diagnostic interpretation of arthroscopic ultrasound imaging and provide information necessary for development of models describing ultrasound propagation within cartilage.

  • 35.
    Jortikka, Matti
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Inkinen, Ritva
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Pathology, University of Kuopio, Kuopio, Finland.
    Haapala, Jussi
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Kiviranta, Ilkka
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Immobilisation causes longlasting matrix changes both in the immobilised and contralateral joint cartilage.1997In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 56, no 4, 255-261 p., 9165998Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The capacity of articular cartilage matrix to recover during 50 weeks of remobilisation after an atrophy caused by 11 weeks of immobilisation of the knee (stifle) joint in 90 degrees flexion starting at the age of 29 weeks, was studied in young beagle dogs.

    METHODS: Proteoglycan concentration (uronic acid) and synthesis ([35S]sulphate incorporation) were determined in six and three knee joint surface locations, respectively. Proteoglycans extracted from the cartilages were characterised by chemical determinations, gel filtration, and western blotting for chondroitin sulphate epitope 3B3.

    RESULTS: The proteoglycan concentrations that were reduced in all sample sites immediately after the immobilisation, remained 14-28% lower than controls after 50 weeks of remobilisation in the patella, the summit of medial femoral condyle, and the superior femoropatellar surface. In the contralateral joint, there was a 49% increase of proteoglycans in the inferior femoropatellar surface after remobilisation, while a 34% decrease was simultaneously noticed on the summit of the medial femoral condyle. Total proteoglycan synthesis was not significantly changed after immobilisation or 50 weeks' remobilisation in the treated or contralateral joint, compared with age matched controls. The chondroitin 6- to 4- sulphate ratio was reduced by immobilisation both in the radioactively labelled and the total tissue proteoglycans. In the remobilised joint, this ratio was restored in femur, while in tibia it remained at a level lower than controls. Neither immobilisation nor remobilisation induced epitopes recognised by the monoclonal antibody 3B3 on native (undigested) proteoglycans.

    CONCLUSION: These results show that the depletion of proteoglycans observed after 11 weeks of immobilisation was not completely restored in certain surface sites after 50 weeks of remobilisation. The significant changes that developed in the contralateral joint during the remobilisation period give further support to the idea that a permanent alteration of matrix metabolism results even from a temporary modification of loading pattern in immature joints.

  • 36.
    Jortikka, Matti
    et al.
    epartment of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    epartment of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    epartment of Anatomy, University of Kuopio, Kuopio, Finland.
    Lahtinen, Risto
    epartment of Anatomy, University of Kuopio, Kuopio, Finland.
    Tammi, Markku
    epartment of Anatomy, University of Kuopio, Kuopio, Finland.
    A high sensitivity dot-blot assay for proteoglycans by cuprolinic blue precipitation.1993In: Connective Tissue Research, ISSN 0300-8207, E-ISSN 1607-8438, Vol. 29, no 4, 263-272 p., 8269703Article in journal (Refereed)
    Abstract [en]

    A highly sensitive blot-assay was developed for glycosaminoglycans (GAGs) and proteoglycans (PGs) utilizing a precipitation reaction by a cationic dye Cuprolinic Blue. The precipitates were deposited into 1-2 mm2 spots on nitrocellulose membrane by using a 96-well filtration apparatus. The dried sheet was digitized by a flat bed scanner and the intensity of the dots was quantitated by an image analysis software. The working range for chondroitin sulfate was 10-300 ng. The response of various GAGs differed according to the number of anionic groups, both sulphate and carboxyl groups being able to bind the dye. The sensitivity of the assay was decreased by high concentrations of GuC, CsC and protein, but not by nonionic detergents, common buffers and 8 M urea. Contact exposure to autoradiography film enabled quantitation of 25-250 DPM, and 1-10 DPM, of 35SO4-radioactivity in precipitated PGs after overnight and 14 days' exposures, respectively.

  • 37.
    Jortikka, Matti
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Parkkinen, Jyrki
    Department of Pathology, University of Kuopio, Kuopio, Finland.
    Inkinen, Rtiva
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Kärner, Jüri
    Department of Zoology, University of Tartu, Tartu, Estonia.
    Järveläinen, Hannu
    Department of Medicine, University of Turku, Finland; Medical Biochemistry, University of Turku, Finland.
    Nelimarkka, Lassi
    Medical Biochemistry, University of Turku, Finland.
    Tammi, Markku
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    The role of microtubules in the regulation of proteoglycan synthesis in chondrocytes under hydrostatic pressure.2000In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 374, no 2, 172-180 p., 10666295Article in journal (Refereed)
    Abstract [en]

    Chondrocytes of the articular cartilage sense mechanical factors associated with joint loading, such as hydrostatic pressure, and maintain the homeostasis of the extracellular matrix by regulating the metabolism of proteoglycans (PGs) and collagens. Intermittent hydrostatic pressure stimulates, while continuous high hydrostatic pressure inhibits, the biosynthesis of PGs. High continuous hydrostatic pressure also changes the structure of cytoskeleton and Golgi complex in cultured chondrocytes. Using microtubule (MT)-affecting drugs nocodazole and taxol as tools we examined whether MTs are involved in the regulation of PG synthesis in pressurized primary chondrocyte monolayer cultures. Disruption of the microtubular array by nocodazole inhibited [(35)S]sulfate incorporation by 39-48%, while MT stabilization by taxol caused maximally a 17% inhibition. Continuous hydrostatic pressure further decreased the synthesis by 34-42% in nocodazole-treated cultures. This suggests that high pressure exerts its inhibitory effect through mechanisms independent of MTs. On the other hand, nocodazole and taxol both prevented the stimulation of PG synthesis by cyclic 0. 5 Hz, 5 MPa hydrostatic pressure. The drugs did not affect the structural and functional properties of the PGs, and none of the treatments significantly affected cell viability, as indicated by the high level of PG synthesis 24-48 h after the release of drugs and/or high hydrostatic pressure. Our data on two-dimensional chondrocyte cultures indicate that inhibition of PG synthesis by continuous high hydrostatic pressure does not interfere with the MT-dependent vesicle traffic, while the stimulation of synthesis by cyclic pressure does not occur if the dynamic nature of MTs is disturbed by nocodazole. Similar phenomena may operate in cartilage matrix embedded chondrocytes.

  • 38.
    Julkunen, Petro
    et al.
    Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland; Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland.
    Harjula, Terhi
    Department of Anatomy, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Iivarinen, Jarkko
    Department of Anatomy, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Marjanen, Juho
    Department of Anatomy, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Seppänen, Kari
    Department of Biosciences, Laboratory of Chemistry, University of Kuopio, Kuopio, Finland.
    Närhi, Tommi
    Department of Anatomy, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Arokoski, Jari
    Department of Physical and Rehabilitation Medicine, Kuopio University Hospitsl, Kuopio, Finland; Institute of Clinical Medicine, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Finland; Biocenter Kuopio, University of Kuopio, Finland.
    Brama, Pieter
    Section of Veterinary Clinical Studies, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Dublin, Ireland.
    Jurvelin, Jukka
    Department of Physics, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Biomechanical, biochemical and structural correlations in immature and mature rabbit articular cartilage.2009In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 17, no 12, 1628-1638 p., 19615962Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The structure and composition of articular cartilage change during development and growth. These changes lead to alterations in the mechanical properties of cartilage. In the present study, biomechanical, biochemical and structural relationships of articular cartilage during growth and maturation of rabbits are investigated.

    DESIGN: Articular cartilage specimens from the tibial medial plateaus and femoral medial condyles of female New Zealand white rabbits were collected from seven age-groups; 0 days (n=29), 11 days (n=30), 4 weeks (n=30), 6 weeks (n=30), 3 months (n=24), 6 months (n=24) and 18 months (n=19). The samples underwent mechanical testing under creep indentation. From the mechanical response, instantaneous and equilibrium moduli were determined. Biochemical analyses of tissue collagen, hydroxylysylpyridinoline (HP) and pentosidine (PEN) cross-links in full thickness cartilage samples were conducted. Proteoglycans were investigated depth-wise from the tissue sections by measuring the optical density of Safranin-O-stained samples. Furthermore, depth-wise collagen architecture of articular cartilage was analyzed with polarized light microscopy. Finite element analyses of the samples from different age-groups were conducted to reveal tensile and compressive properties of the fibril network and the matrix of articular cartilage, respectively.

    RESULTS: Tissue thickness decreased from approximately 3 to approximately 0.5mm until the age of 3 months, while the instantaneous modulus increased with age prior to peak at 4-6 weeks. A lower equilibrium modulus was observed before 3-month-age, after which the equilibrium modulus continued to increase. Collagen fibril orientation angle and parallelism index were inversely related to the instantaneous modulus, tensile fibril modulus and tissue thickness. Collagen content and cross-linking were positively related to the equilibrium compressive properties of the tissue.

    CONCLUSIONS: During maturation, significant modulation of tissue structure, composition and mechanical properties takes place. Importantly, the present study provides insight into the mechanical, chemical and structural interactions that lead to functional properties of mature articular cartilage.

  • 39.
    Julkunen, Petro
    et al.
    Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland; Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland.
    Wilson, Wouter
    Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
    Jurvelin, Jukka
    Department of Physics, University of Kuopio, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
    Rieppo, Jarno
    Department of Biomedicine, Anatomy, University of Kuopio, Kuopio, FinlandDepartment of Biomedicine, Anatomy, University of Kuopio, Kuopio, Finland.
    Qu, Cheng-Juan
    Department of Biomedicine, Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Biosciences, Applied Biotechnology, University of Kuopio, Kuopio, Finland.
    Korhonen, Rami
    Department of Physics, University of Kuopio, Kuopio, Finland; Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.
    Stress-relaxation of human patellar articular cartilage in unconfined compression: prediction of mechanical response by tissue composition and structure.2008In: Journal of Biomechanics, ISSN 0021-9290, E-ISSN 1873-2380, Vol. 41, no 9, 1978-86 p., 18490021Article in journal (Refereed)
    Abstract [en]

    Mechanical properties of articular cartilage are controlled by tissue composition and structure. Cartilage function is sensitively altered during tissue degeneration, in osteoarthritis (OA). However, mechanical properties of the tissue cannot be determined non-invasively. In the present study, we evaluate the feasibility to predict, without mechanical testing, the stress-relaxation response of human articular cartilage under unconfined compression. This is carried out by combining microscopic and biochemical analyses with composition-based mathematical modeling. Cartilage samples from five cadaver patellae were mechanically tested under unconfined compression. Depth-dependent collagen content and fibril orientation, as well as proteoglycan and water content were derived by combining Fourier transform infrared imaging, biochemical analyses and polarized light microscopy. Finite element models were constructed for each sample in unconfined compression geometry. First, composition-based fibril-reinforced poroviscoelastic swelling models, including composition and structure obtained from microscopical and biochemical analyses were fitted to experimental stress-relaxation responses of three samples. Subsequently, optimized values of model constants, as well as compositional and structural parameters were implemented in the models of two additional samples to validate the optimization. Theoretical stress-relaxation curves agreed with the experimental tests (R=0.95-0.99). Using the optimized values of mechanical parameters, as well as composition and structure of additional samples, we were able to predict their mechanical behavior in unconfined compression, without mechanical testing (R=0.98). Our results suggest that specific information on tissue composition and structure might enable assessment of cartilage mechanics without mechanical testing.

  • 40.
    Järvinen, Kristiina
    et al.
    Department of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Jokiniemi, Jorma
    Deaprtment of Environmental Science.
    Lammi, Mikko
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Lappalainen, Reijo
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Närvänen, Ale
    Department of Pharmacy, University of Eastern Finland.
    Pakkanen, Tapani
    Department of Chemistry, University of Eastern Finland, Kuopio,Finland.
    Lehto, Vesa-Pekka
    Department ofApplied Physics, University of Eastern Finalnd, Kuopio, Finland.
    Nanoteknologia biomateriaalien ja lääkkeiden kantaja-aineiden pintojen räätälöinnissä [Nanoscale tailoring of the surface properties of biomaterials and drug carriers]2012In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 128, no 20, 2085-2092 p., 23167167Article, review/survey (Refereed)
    Abstract [en]

    Functionalities of biomaterials and drug delivery systems are improved by tailoring their surface properties using modern nanotechnology. Orthopedic implants and invasive electrodes are examples of implantable biomaterials. Biological interactions of orthopedic implants can be optimized by the synergetic effect of surface micro- and nanotexturing with a chemical composition of coating. Further, mechanical flexibility and electrochemical characteristics of invasive electrodes are improved by using micro- and nanotechnology. In nano-size drug delivery systems, surface properties of nanocarriers strongly affect their safety and efficacy. Mesoporous silicon nanoparticles are example of nanocarriers those properties can be tailored for drug delivery applications.

  • 41.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Elo, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Stress responses of mammalian cells to high hydrostatic pressure.2003In: Biorheology, ISSN 0006-355X, E-ISSN 1878-5034, Vol. 40, no 1-3, 87-92 p., 12454391Article in journal (Refereed)
    Abstract [en]

    High hydrostatic pressure causes stress response in many types of mammalian cells. We have previously shown that an accumulation of heat shock protein 70 (Hsp70) in a chondrocytic cell line occurred without an activation of the gene itself. Stabilization of the hsp70 mRNA was shown to be the reason for the Hsp70 stress response in the pressurized cells. Since accumulation of Hsp70 in pressurized cells indicated that high hydrostatic pressure induces a stress response without heat shock transcription factor activation, we decided to investigate the activation of two other stress-associated transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). Induction of Hsp70 in immortalized and primary chondrocytes, murine Neuro-2a neuroblastoma and HeLa cervical carcinoma cell lines was investigated at both mRNA and protein levels. In immortalized chondrocytes and HeLa cells, hsp70 mRNA levels were clearly elevated after 6 hours of the onset of 30 MPa continuous hydrostatic pressure, while in primary chondrocytes and Neuro-2a cells (the cells known to be stress-sensitive) no induction was observed. Surprisingly, neither heat shock nor high hydrostatic pressure could induce the hsp70 mRNA in Neuro-2a cells, although an activation of heat shock transcription factor could be observed in heat-shocked cells. No activation of the AP-1 and NF-kappaB binding to their target DNA sequences could be shown in the immortalized chondrocytes.

  • 42.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Elo, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Goldring, Mary
    Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
    Eriksson, John
    †Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Sistonen, Lea
    †Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation.1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 5, 2319-2324 p., 9482883Article in journal (Refereed)
    Abstract [en]

    In response to various stress stimuli, heat shock genes are induced to express heat shock proteins (Hsps). Previous studies have revealed that expression of heat shock genes is regulated both at transcriptional and posttranscriptional level, and the rapid transcriptional induction of heat shock genes involves activation of the specific transcription factor, heat shock factor 1 (HSF1). Furthermore, the transcriptional induction can vary in intensity and kinetics in a signal- and cell-type-dependent manner. In this study, we demonstrate that mechanical loading in the form of hydrostatic pressure increases heat shock gene expression in human chondrocyte-like cells. The response to continuous high hydrostatic pressure was characterized by elevated mRNA and protein levels of Hsp70, without activation of HSF1 and transcriptional induction of hsp70 gene. The increased expression of Hsp70 was mediated through stabilization of hsp70 mRNA molecules. Interestingly, in contrast to static pressurization, cyclic hydrostatic loading did not result in the induction of heat shock genes. Our findings show that hsp70 gene expression is regulated posttranscriptionally without transcriptional induction in chondrocyte-like cells upon exposure to high continuous hydrostatic pressure. We suggest that the posttranscriptional regulation in the form of hsp70 mRNA stabilization provides an additional mode of heat shock gene regulation that is likely to be of significant importance in certain forms of stress.

  • 43.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Holmberg, Carina
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Eriksson, John
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biology, University of Turku, Turku, Finland.
    Sistonen, Lea
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Protein synthesis is required for stabilization of hsp70 mRNA upon exposure to both hydrostatic pressurization and elevated temperature.2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 475, no 3, 283-286 p., 10869572Article in journal (Refereed)
    Abstract [en]

    We have recently described that in chondrocytic cells high hydrostatic pressure (HP) causes a heat shock response via mRNA stabilization without a transcriptional activation of the hsp70 gene. In this study, we investigated whether this exceptional regulatory mechanism occurs more generally in different types of cells. Indeed, hsp70 mRNA and protein accumulated in HeLa, HaCat and MG-63 cells under 30 MPa HP, without DNA-binding of heat shock transcription factor 1 (HSF1) to the heat shock element of the hsp70 gene or formation of nuclear HSF1 granules, revealing a lack of transcriptional activation. Moreover, we observed that protein synthesis is needed for mRNA stabilization. Thus, high HP offers a model to study the mechanisms of hsp70 mRNA stabilization without HSF1-mediated induction of the heat shock gene response.

  • 44.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Holmberg, Carina
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Eriksson, John
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Sistonen, Lea
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland; Department of Biology, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Primary chondrocytes resist hydrostatic pressure-induced stress while primary synovial cells and fibroblasts show modified Hsp70 response.2001In: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 9, no 1, 7-13 p., 11178942Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: During joint loading, chondrocytes in the articular cartilage are subjected to gradients of high compressive hydrostatic pressure (HP). In response to diverse chemical or physical stresses, heat shock genes are induced to express heat shock proteins (Hsps). This study sought to examine the role of Hsps in baroresistance in primary bovine chondrocytes and synovial cells, as well as in primary human fibroblasts.

    METHODS: Northern blotting was used to analyze the steady-state levels of hsp70 mRNA in the primary cells exposed to HP or heat stress. Hsp70 protein accumulation was analyzed by Western blotting, and the DNA-binding activity was examined by gel mobility shift assay.

    RESULTS: Primary bovine chondrocytes which have been adapted to live under pressurized conditions showed negligible Hsp70 response upon HP loading, whereas primary bovine synovial cells and human fibroblasts accumulated hsp70 mRNA and protein when subjected to HP. The response was initiated without activation of the heat shock transcription factor 1. Interestingly, pre-conditioning of the barosensitive fibroblasts with HP or heat shock reduced the Hsp70 response, indicating induction of baroresistance.

    CONCLUSION: This study suggests that Hsp70 can play an important role in the early stages of adaptation of cells to HP. Thus, the Hsp70 gene expression upon HP loading may serve as one indicator of the chondrocytic phenotype of the cells. This can be of use in the treatment of cartilage lesions.

  • 45.
    Kaarniranta, Kai
    et al.
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Ihanamäki, Tapio
    Department of Ophthalmology, Helsinki University Hospital, Helsinki, Finland.
    Sahlman, Janne
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Pulkkinen, Hertta
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Uusitalo, Hannu
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Arita, Machiko
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
    Tammi, Raija
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Chondrogenic and Osteogenic Differentiation Group.
    Helminen, Heikki
    Chondrogenic and Osteogenic Differentiation Group.
    A mouse model for Stickler's syndrome; ocular phenotype of mice carrying a targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1).2006In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 83, no 2, 297-303 p., 16546167Article in journal (Refereed)
    Abstract [en]

    The influences of targeted heterozygous inactivation of type II (pro)collagen gene (Col2a1) on eye structures in the 15-month-old C57BL/6JOlaHsd mouse was studied. The eyes were collected from C57BL mice heterozygous for a targeted inactivation of one allele of the Col2a1 gene (Col2a1(+/-) mice). The eyes of C57BL mice with normal gene alleles were used as controls (Col2a1(+/+) mice). Ocular histology was analyzed from tissue sections, stained with hematoxylin and eosin, toluidine blue and alcian blue. Type II collagen was localized by immunohistochemistry. Hyaluronan (HA) was stained utilizing the biotinylated complex of the hyaluronan-binding region of aggrecan and link protein (bHABC). The anterior segment of the eye was well-formed in both genotypes, but typical folding of ciliary processes was decreased, while increased stromal extracellular matrix vacuolization was seen in the Col2a1(+/-) mice. In the lens of these mice, subcapsular extracellular matrix changes were observed. Differences in retinal structures or the number of the eyes with retinal detachment were not detected between the genotypes. In Col2a1(+/-) mice, staining for type II collagen was weaker in cornea, ciliary body, iris, lens, vitreous, retina, choroid and sclera than in the control mice. HA staining was detected in the extraocular tissues, ciliary body, iris and the choroid of both genotypes. HA staining was observed only in the vitreous body of the control animals. Heterozygous inactivation of Col2a1 gene causes structural defects in the murine eye. The observed structural changes in the ciliary body, lens and vitreous of the Col2a1(+/-) mice may represent ocular features found in the human Stickler syndrome, where the abnormalities result from COL2A1 gene mutations which lead to functional haploinsufficiency.

  • 46.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Oksala, Niku
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Suuronen, Tiina
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Sistonen, Lea
    Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Salminen, Antero
    Department of Neurology, Kuopio University Hospital, Kuopio, Finland; Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Neuronal cells show regulatory differences in the hsp70 gene response.2002In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 101, no 1-2, 136-140 p., 12007842Article in journal (Refereed)
    Abstract [en]

    The synthesis of heat shock proteins (Hsps), encoded by heat shock genes, is increased in response to various stress stimuli. Hsps function as molecular chaperones, they dissociate cytotoxic stress-induced protein aggregates within cells and ensure improved survival. Induction of heat shock genes is mainly regulated at the transcriptional level. The stress responsive transcription factor, heat shock factor 1 (HSF1), is involved in the transcriptional induction of the heat shock genes. Our objective was to examine how hsp70 genes are regulated in different transformed and primary neurons upon exposure to elevated temperature. Our findings reveal that the Hsp70 response is regulated at the translational level in Neuro-2a neuroblastoma cells, while the IMR-32 neuroblastoma cells respond to stress by the classical HSF1-driven transcriptional regulatory mechanism. Primary rat hippocampal neurons show a lack of HSF1 and induction of the hsp70 gene. These observations suggest that neuronal cells display different hsp70 gene expression patterns which range from undetected response to transcriptional and posttranscriptional regulation during heat stress.

  • 47.
    Kaarniranta, Kai
    et al.
    Department of Anatomy, University of Kuopio, Kuopio,Finland; Department of Neurosciences and Neurology, University of Kuopio, Kuopio, Finland.
    Oksala, Niku
    Department of Surgery, Kuopio University Hospital, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Sistonen, Lea
    Department of Cell Biology, Åbo Academi, Turku, Finland; Center of Biotechnology, University of Turku, Turku, Finland.
    Solustressin tutkimuksesta kliinisiin läpimurtoihin? [From research of cellular stress to various clinical break through innovations?]2001In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 117, no 22, 2266-2272 p., 12183959Article, review/survey (Refereed)
    Abstract [fi]

    Fysikaalisen tai kemiallisen stressin seurauksena useiden geenien aktiivisuus vähenee,kun taas lämpösokki- eli stressigeenien induktio lisääntyy. Stressigeenit koodaavat lämpösokkiproteiineja(Hsp), jotka toimivat soluissa kaperoneina, »avustajina», auttaensolujen proteiineja laskostumaan oikein translaatiossa, kalvon läpi kuljetuksessa tai esimerkiksikorkean lämpötilan aiheuttaman vaurion jälkeen. Viime vuosina lämpösokkiproteiinienkliininen merkitys useiden sairauksien patogeneesissä, diagnostiikassa ja ennusteenmäärittämisessä on alkanut selvitä. Merkittävimmät kliiniset löydökset liittyvätiskeemisiin prosesseihin, kuten sydän- ja aivoinfarkteihin, useisiin neoplasioihin ja ikääntymiseen.Tässä katsauksessa käsittelemme stressigeenien säätelyä, Hsp70-stressiproteiinienkliinisiä yhteyksiä ja niiden mahdollisia hoitosovelluksia iskeemisissä, neoplastisissaja degeneratiivisissa prosesseissa.

  • 48.
    Kaarniranta, Kai
    et al.
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Ryhänen, Tuomas
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Suuronen, Tiina
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Huhtala, Anne
    University of Tampere Medical School, Tampere, Finland.
    Kontkanen, Matti
    Department of Ophthalmology, North Karelia Central Hospital, Joensuu, Finland.
    Teräsvirta, Markku
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Uusitalo, Hannu
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland.
    Salminen, Antero
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
    Geldanamycin increases 4-hydroxynonenal (HNE)-induced cell death in human retinal pigment epithelial cells.2005In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 382, no 1-2, 185-190 p., 15911146Article in journal (Refereed)
    Abstract [en]

    Development of age-related macular degeneration (AMD) is associated with functional abnormalities and cell death in retinal pigment epithelial (RPE) cells attributable to oxidative stress. To minimize the adverse effects of oxidative stress, cells activate their defence systems, e.g., via increased expression of heat shock protein (Hsp), activation of stress sensitive AP-1 and NF-kappaB transcription factors. In this study, we examined the accumulation of Hsp70 protein, activation of AP-1 and NF-kappaB transcription factors in human ARPE-19 cells subjected to a 4-hydroxynonenal (HNE)-induced oxidative stress. In addition, the influence of Hsp90 inhibitor geldanamycin (GA) was studied in HNE-treated cells. Mitochondrial metabolic activity and apoptosis were determined to evaluate cell death in the ARPE-19 cells. The ARPE-19 cells showed increased accumulation of Hsp70 protein before of the cytotoxic hallmarks appearing in response to HNE. In contrast, increased DNA-binding activities of AP-1 or NF-kappaB transcription factors were not seen under HNE insults. Interestingly, GA significantly increased cell death in the HNE-treated cells, which was involved in caspase-3 independent apoptosis. This study reveals that the Hsps have an important role in the cytoprotection of RPE cells subjected to HNE-derived oxidative stress.

  • 49.
    Kaarniranta, Kai
    et al.
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Ryhänen, Tuomas
    Department of Ophthalmology, University of Kuopio, Kuopio, Finland.
    Sironen, Reijo
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Suuronen, Tiina
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
    Elo, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Karjalainen, Hannu
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Teräsvirta, Markku
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
    Uusitalo, Hannu
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
    Salminen, Antero
    Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
    Geldanamycin activates Hsp70 response and attenuates okadaic acid-induced cytotoxicity in human retinal pigment epithelial cells.2005In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 137, no 1-2, 126-131 p., 15950770Article in journal (Refereed)
    Abstract [en]

    Reversible protein phosphorylation regulates the biological activities of many human proteins involved in crucial cellular processes, e.g., protein-protein interactions, cell signaling, gene transcription, cell growth, and death. A malfunction of cellular homeostasis in retinal pigment epithelial (RPE) cells is involved in the age-related retinal degeneration. In this study, we examined cytotoxicity in human RPE cells subjected to the protein phosphatase inhibitor, okadaic acid (OA). Moreover, the influence of Hsp90 inhibitor geldanamycin (GA), a benzoquinone ansamycin, in cytoprotection was assessed. Hsp70 protein levels were analyzed by Western blot. Cellular viability was determined by LDH and MTT assays. To study apoptotic cell death, caspase-3 enzyme activity was measured by assaying the cleavage of a fluorescent peptide substrate and Hoechst dye was used to visualize nuclear morphology. OA treatment caused morphological changes and induced cytotoxicity by caspase-3-independent manner in the RPE cells. No evidence of nuclear fragmentation was observed in response to OA. Interestingly, GA treatment accumulated Hsp70 protein and attenuated OA-induced cytotoxicity. This study suggests that Hsp70 and Hsp90 are closely related to cytoprotection of RPE cells in response to protein phosphatase inhibition.

  • 50.
    Kaarniranta, Kai
    et al.
    North-Carelia Central Hospital, Eye Clinic, Joensuu, Finland.
    Sihvola, Roope
    North-Carelia Central Hospital, Eye Clinic, Joensuu, Finland.
    Salminen, Antero
    Department of Neurosciences and Neurology, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Teräsvirta, Markku
    Eye Clinic, Kuopio University Hospital, Kuopio, Finland.
    Kontkanen, Matti
    North-Carelia Central Hospital, Eye Clinic, Joensuu, Finland.
    Silmäpohjan rappeumatauti - vaikea ongelma lääkärille [Age-related macular degeneration--a difficult problem for the patient and for the ophthalmologist].2003In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 119, no 10, 935-942 p., 12833783Article in journal (Refereed)
    Abstract [fi]

    Silmänpohjan ikärappeuma on yleisin näkövammaisuutta aiheuttava silmäsairaus länsimaissa. Yli 65-vuotiaista 10–20 % kärsii sen aiheuttamista keskeisen näköalueen korjaantumattomista häiriöistä. Väestön vanhetessa ikärappeuman esiintyvyys on lisääntynyt. Sairauden kliiniset ja histopatologiset muutokset tunnetaan hyvin, mutta etiologia on tuntematon, ehkäisystä on niukasti tietoa ja hoitovaihtoehdot ovat vähäiset. Silmänpohjan ikärappeumasta on muodostunut yksi vaikeimmista ongelmista silmälääkäreille ja oftalmologian tutkijoille.

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