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  • 1. Brage, M
    et al.
    Lie, Anita
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Ransjö, Maria
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Kasprzykowski, F
    Kasprzykowska, R
    Abrahamson, M
    Grubb, A
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Osteoclastogenesis is decreased by cysteine proteinase inhibitors2004In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 34, no 3, p. 412-24Article in journal (Refereed)
    Abstract [en]

    The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.

  • 2. Brand, HS
    et al.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Grubb, A
    Beertsen, W
    Nieuw Amerongen, AV
    Everts, V
    Family 2 cystatins inhibit osteoclast-mediated bone resorption in calvarial bone explants.2004In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 35, no 3, p. 689-696Article in journal (Refereed)
    Abstract [en]

    Osteoclastic bone resorption depends on the activity of various proteolytic enzymes, in particular those belonging to the group of cysteine proteinases. Biochemical studies have shown that cystatins, naturally occurring inhibitors of these enzymes, inhibit bone matrix degradation. Since the mechanism by which cystatins exert this inhibitory effect is not completely resolved yet, we studied the effect of cystatins on bone resorption microscopically and by Ca-release measurements. Calvarial bone explants were cultured in the presence or absence of family 2 cystatins and processed for light and electron microscopic analysis, and the culture media were analyzed for calcium release. Both egg white cystatin and human cystatin C decreased calcium release into the medium significantly. Microscopic analyses of the bone explants demonstrated that in the presence of either inhibitor, a high percentage of osteoclasts was associated with demineralized non-degraded bone matrix. Following a 24-h incubation in the presence of cystatin C, 41% of the cells were adjacent to areas of demineralized non-degraded bone matrix, whereas in controls, this was only 6%. If bone explants were cultured with both PTH and cystatin C, 60% of the osteoclasts were associated with demineralized non-degraded bone matrix, compared to 27% for bones treated with PTH only (P < 0.01). Our study provides evidence that cystatins, the naturally occurring inhibitors of cysteine proteinases, reversibly inhibit bone matrix degradation in the resorption lacunae adjacent to osteoclasts. These findings suggest the involvement of cystatins in the modulation of osteoclastic bone degradation.

  • 3.
    Brechter, Anna Bernhold
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lundgren, Inger
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-kappaB and MAP kinases.2008In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 43, no 1, p. 72-83Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg10-Lys-BK (DALBK), IL-1beta and TNF-alpha have been investigated. IL-1beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1beta and TNF-alpha activated NF-kappaB and AP-1 in MG-63 cells. IL-1beta stimulated NF-kappaB via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappaB, p38 and JNK were important for IL-1beta induced stimulation of B1 receptors, and NF-kappaB and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappaB, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappaB and MAP kinase pathways, but that signal transduction pathways are different for IL-1beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis.

  • 4. Conaway, H. Herschel
    et al.
    Henning, Petra
    Lie, Anita
    Umeå University, Faculty of Medicine, Department of Odontology.
    Tuckermann, Jan
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 93, p. 43-54Article in journal (Refereed)
    Abstract [en]

    Glucocorticoid (GC) therapy is the greatest risk factor for secondary osteoporosis. Pathogenic mechanisms involve an initial increase in bone resorption followed by decreased bone formation. To gain a better understanding of the resorptive activity of GCs, we have used mouse bone marrow macrophages (BMM) to determine if GCs can directly modulate RANKL stimulated osteoclast formation and/or activity. In agreement with previous studies, experiments performed in plastic wells showed that GCs (dexamethasone, hydrocortisone, and prednisolone) inhibited osteoclast number and size during the initial phases of RANKL stimulated osteoclastogenesis; however, in prolonged cultures, decreased apoptosis was observed and escape from GC induced inhibition occurred with an enhanced number of osteoclasts formed, many with an increased area. When BMM cells were seeded on bone slices, GCs robustly enhanced RANKL stimulated formation of resorption pits and release of CTX without affecting the number or size of osteoclasts formed and with no effect on apoptosis. Stimulation of pit formation was not associated with increased life span of osteoclasts or an effect on mRNA expression of several osteoclastic or osteoclastogenic genes. The potentiation of RANKL induced CTX release by dexamethasone was significantly less in BMM cells from mice with conditional knockout of the osteoclastic glucocorticoid receptor and completely absent in cells from Gem mice, which carry a point mutation in one dimerizing interface of the GC receptor. These data suggest that: 1. Plastic is a poor medium to use for studying direct effects of GCs on osteoclasts 2. GCs can enhance bone resorption without decreasing apoptosis, and 3. A direct enhancement of RANKL mediated resorption is stimulated by the dimeric GC -receptor.

  • 5.
    Eklund, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Bone mass, size and previous fractures as predictors of prospective fractures in an osteoporotic referral population.2009In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 45, no 4, p. 808-813Article in journal (Refereed)
    Abstract [en]

    The influence of bone mass, bone size and previous low energy fractures upon prospective fractures has not been investigated in a referral osteoporotic population. We investigated the association between bone mass, bone size, previous fractures, body constitution, and prospective validated fractures in 5701 women and 1376 men, aged 30 years and older. Bone mass measurements of the femoral neck were collected at a single study center in Sweden. Most of the subjects were measured on suspicion of osteoporosis. Data on validated low energy retrospective and prospective fractures in the cohort were collected from the corresponding health care district. Bone mineral density (BMD, g/cm(2)) and estimated volumetric BMD (vBMD, g/cm(3)) were shown to be good independent predictors for fracture in both women and men (Hazard ratio per standard deviation decrease (HR)=1.27-1.52, p<0.05). Bone size did not predict prospective fractures in either sex (HR=0.91-0.99, p>0.05), and bone size completely explained the higher BMD in men than in women. In women, retrospective low energy fractures (HR=1.78, p<0.001) and height (HR=1.02, p=0.006) were additional independent predictors of osteoporotic fractures after adjusting for age and BMD. In conclusion, we show that in a large osteoporotic referral population, age, BMD and previous fractures are independent predictors of prospective low energy fractures. These results add additional strength to the recent change in focus towards a multivariate analysis when assessing the future risk of fracture.

  • 6.
    Granholm, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henning, Petra
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Osteoclast progenitor cells present in significant amounts in mouse calvarial osteoblast isolations and osteoclastogenesis increased by BMP-22013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 52, no 1, p. 83-92Article in journal (Refereed)
    Abstract [en]

    Enzymatically released cells from neonatal mouse calvarial bones are frequently used as primary mouse osteoblasts for in vitro studies. We, here, report that although these cells lack mRNA expression of the osteoclastic genes Calcr, Acp5 and Mmp-9 at early time points after their isolation, these transcripts are gradually upregulated when the calvarial osteoblast cultures are differentiated to more mature osteoblasts in long term cultures. Similarly, Calcr, Acp5, Mmp-9, as well as Rank and Nfatc1 mRNA expressions are robustly increased when the osteoblast cultures were induced to differentiate by treatment with bone morphogenetic protein (BMP-2). The increased Calcr mRNA resulted in functionally active calcitonin receptors. Enhanced osteoblastic differentiation was associated with increased Rankl mRNA expression and decreased Opg and Cfs1 mRNA expression. Treatment of the osteoblastic cells with BMP-2 or RANKL, either on plastic dishes or bone slices, resulted in the formation of multinucleated tartrate-resistant acid phosphatase positive cells, which were able to excavate resorption pits and release CTX from the bones. In contrast, increased osteoblastic differentiation induced by BMP-2 in the mouse calvarial osteoblastic cell line MC3T3-E1 was not associated with increased mRNA expression of Calcr, Acp5, Rank, c-Fms or Oscar. Interestingly, Ctsk mRNA was increased during osteoblastic differentiation in both mouse calvarial osteoblast cultures and in MC3T3-E1 cultures. Also osteoblasts isolated from mouse long bones by outgrowth from explant cultures were contaminated with osteoclast progenitors able to differentiate into bone resorbing osteoclasts. These data indicate that mouse calvarial osteoblast cultures contain osteoclast progenitor cells, which will be differentiated along the osteoclastic lineage during osteoblastic differentiation. Moreover, the data show that BMP-2 not only stimulates osteoblastic differentiation but can also induce osteoclastogenesis through increased RANKL.

  • 7. Henning, P.
    et al.
    Kindlund, B.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Conaway, H. H.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Inhibition of osteoclast formation in human peripheral CD14+cells by vitamin A2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S92-S92Article in journal (Refereed)
  • 8.
    Johansson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Objectively measured physical activity is associated with parameters of bone in 70-year-old men and women2015In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 81, p. 72-79Article in journal (Refereed)
    Abstract [en]

    As the world's population ages, the occurrence of osteoporosis-related fractures is projected to increase. Low areal bone mineral density (aBMD), a well-known risk factor for fractures, may be influenced by physical activity (PA). In this cross-sectional study, we aimed to investigate potential associations between objective measures of PA and bone properties, in a population-based cohort of 1228 70-year-old men and women. We measured volumetric BMD (vBMD, mg/cm3) together with cross-sectional area (CSA, mm2) by peripheral quantitative computed tomography at sites located 4% and 66% in the distal–proximal trajectory at the tibia and radius. We also measured aBMD (g/cm2) by dual energy X-ray absorptiometry at the femoral neck, lumbar spine (L1–L4) and radius. Participants wore triaxial accelerometers for 7 consecutive days to obtain objective estimates of PA. The intensity of the objective PA was divided into light (100–1951 counts/min [CPM]), moderate (1952– 5724 cpm) and vigorous (≥5725 cpm). Maximal accelerations for the anterior–posterior (z), medio-lateral (x), and vertical (y) axes were also separately assessed. Associations were investigated using bivariate correlations and multiple linear regression, adjusted for height, weight and sex. Vigorous PA showed the strongest association with femoral neck aBMD (β = 0.09, p b 0.001), while both moderate and vigorous PAs were associated with cor- tical area and trabecular vBMD in the weight-bearing tibia (all p b 0.05). Peak vertical accelerations were associated significantly with cortical area (β = 0.09, p b 0.001) and trabecular vBMD (β = 0.09, p = 0.001) of the tibia, whereas peak anterior–posterior accelerations showed no correlation with these properties. No positive association was found between objectively measured PA and bone parameters of the radius. In conclusion, vertical accelerations and moderate to vigorous PA independently predict bone properties, especially in the weight-bearing tibia, in 70-year-old men and women. 

  • 9.
    Kassem, Ali
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lunberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lindholm, C.
    Souza, P.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Regulation of osteoclast formation by toll-like receptors 2 and 52012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S67-S67Article in journal (Refereed)
  • 10.
    Kassem, Ali
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lunberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lindholm, C.
    Souza, P.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Regulation of osteoclast formation by toll-like receptors 2 and 52012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S86-S87Article in journal (Refereed)
  • 11.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Baldock, P.
    Garvan Institute of Medical Research, Darlinghurst, New South Wales.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lack of CD47 leads to impaired bone cell differentiation and results in an osteopenic bone phenotype2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S42-S43Article in journal (Refereed)
  • 12.
    Lammi, Pirkko
    et al.
    Department of Clinical Chemistry, Kuopio University Hospital, Kuopio, Finland; Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Lammi, Mikko
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Hyttinen, Mika
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Panula, Harri
    Department of Surgery, Pietarsaari Hospital, Pietarsaari, Finland.
    Kiviranta, Ilkka
    Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland.
    Helminen, Heikki
    Department of Anatomy, University of Kuopio, Kuopio, Finland.
    Site-specific immunostaining for type X collagen in noncalcified articular cartilage of canine stifle knee joint.2002In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 31, no 6, p. 690-696, article id 12531563Article in journal (Refereed)
    Abstract [en]

    Type X collagen is a short-chain collagen that is strongly expressed in hypertrophic chondrocytes. In this study, we used an immunohistochemical technique exploiting a prolonged hyaluronidase unmasking of type X collagen epitopes to show that type X collagen is not restricted to calcified cartilage, but is also present in normal canine noncalcified articular cartilage. A 30 degrees valgus angulation procedure of the right tibia was performed in 15 dogs at the age of 3 months, whereas their nonoperated sister dogs served as controls. Samples were collected 7 and 18 months after the surgery and immunostained for type X collagen. The deposition of type X collagen increased during maturation from age 43 weeks to 91 weeks. In the patella, most of the noncalcified cartilage stained for type X collagen, whereas, in the patellar surface of the femur, it was present mainly in the femoral groove close to cartilage surface. In femoral condyles, the staining localized mostly in the superficial cartilage on the lateral and medial sides, but not in the central weight-bearing area. In tibial condyles, type X collagen was often observed close to the cartilage surface in medial parts of the condyles, although staining could also be seen in the deep zone of the cartilage. Staining for type X collagen appeared strongest at sites where the birefringence of polarized light was lowest, suggesting a colocalization of type X collagen with the collagen fibril arcades in the intermediate zone. No significant difference in type X collagen immunostaining was observed in lesion-free articular cartilage between controls and dogs that underwent a 30 degrees valgus osteotomy. In osteoarthritic lesions, however, there was strong immunostaining for both type X collagen and collagenase-induced collagen cleavage products. The presence of type X collagen in the transitional zone of cartilage in the patella, femoropatellar groove, and in tibial cartilage uncovered by menisci suggests that it may involve a modification of collagen fibril arrangement at the site of collagen fibril arcades, perhaps providing additional support to the collagen network.

  • 13.
    Nordström, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Idrottsmedicin.
    Högström, Magnus
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Idrottsmedicin.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Effects of different types of weight-bearing loading on bone mass and size in young males: A longitudinal study.2007In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 42, no 3, p. 565-571Article in journal (Refereed)
  • 14.
    Olkku, Anu
    et al.
    School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Leskinen, Jarkko
    Department of Physics and Mathematics, University of Eastern Finland, Kuopio, Finland.
    Lammi, Mikko
    Department of Biosciences, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
    Hynynen, Kullervo
    Department of Physics and Mathematics, University of Eastern Finland, Kuopio, Finland; Department of Medical Biophysics, University of Toronto and Imaging Research, Sunnybrook Health Sciences Centre, Toronto, Canada.
    Mahonen, Anitta
    chool of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Finland; Bone and Cartilage Research Unit, University of Eastern Finland, Kuopio, Finland.
    Ultrasound-induced activation of Wnt signaling in human MG-63 osteoblastic cells.2010In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 47, no 2, p. 320-330, article id 20435172Article in journal (Refereed)
    Abstract [en]

    The benefit from an ultrasound (US) exposure for fracture healing has been clearly shown. However, the molecular mechanisms behind this effect are not fully known. Recently, the canonical Wnt signaling pathway has been recognized as one of the essential regulators of osteoblastogenesis and bone mass, and thereby considered crucial for bone health. Mechanical loading and fluid shear stress have been reported to activate the canonical Wnt signaling pathway in bone cells, but previous reports on the effects of therapeutic US on Wnt signaling in general or in bone, in particular, have not been published yet. Therefore, activation of Wnt signaling pathway was assayed in human osteoblastic cells, and indeed, this pathway was found to be activated in MG-63 cells through the phosphoinositol 3-kinase/Akt (PI3K/Akt) and mTOR cascades following a single 10 min US exposure (2 W, 1.035 MHz). In addition to the reporter assay results, the Wnt pathway activation was also observed as nuclear localization of beta-catenin. Wnt activation showed also temperature dependence at elevated temperatures, and the expression of canonical Wnt ligands was induced under the thermal exposures. However, existence of a specific, non-thermal US component was evident as well, perhaps evidence of a potential dual action of therapeutic US on bone. Neither US nor heat exposures affected cell viability in our experiments. In summary, this is the first study to report that Wnt signaling cascade, important for osteoblast function and bone health, is one of the pathways activated by therapeutic US as well as by hyperthermia in human osteoblastic cells. Our results provide evidence for the potential molecular mechanisms behind the beneficial effects of US on fracture healing. Combinations of US, heat, and possible pharmacological treatment could provide useful flexibility for clinical cases in treating various bone disorders.

  • 15.
    Persson, Emma
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Voznesensky, OS
    Huang, YF
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts.2005In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 37, no 4, p. 513-529Article in journal (Refereed)
    Abstract [en]

    Interleukin-6 (IL-6), and the related cytokines IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), are potent stimulators of osteoclastic bone resorption. In the present study, we have addressed the possibility that the neuropeptide vasoactive intestinal peptide (VIP) may regulate the production of and/or sensitivity to the IL-6 family of cytokines in mouse calvarial osteoblasts. VIP stimulated IL-6 mRNA expression and protein release in a time- and concentration-dependent manner, whereas mRNA expression of the IL-6 receptor, as well as mRNA expressions of IL-11, LIF, OSM and their cognate receptors, were unaffected by VIP. In cells transfected with the IL-6 promoter coupled to luciferase, VIP increased transcriptional activity. The effects of VIP were shared by the related neuropeptide PACAP-38, belonging to the same superfamily of neuropeptides, whereas secretin did not have any effect, indicating that the effects were mediated by VPAC2 receptors. The effects of VIP were potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram and mimicked by forskolin, indicating the involvement of the cyclic AMP/protein kinase A pathway. This was further demonstrated by the facts that the stimulatory effect of VIP on luciferase activity could be reversed by the PKA inhibitors H-89 and KT5720 and was mimicked by cyclic AMP analogues selective for PKA, but not by those selective for Epac. In addition, VIP enhanced the phosphorylation of CREB, as assessed by both immunocytochemical analysis and Western blot. The DNA binding activity of nuclear extracts to C/EBP was increased by VIP, whereas binding to AP-1 was decreased. In contrast, DNA binding to NF-kappaB, as well as nuclear translocation of NF-kappaB and C/EBP, were unaffected by VIP. The mRNA expressions of C/EBPbeta, C/EBPdelta, C/EBPgamma, c-Jun, JunB, c-Fos, Fra-1 and IkappaBalpha and protein level of IkappaBalpha were all unaffected by VIP. These observations, together, demonstrate that VIP stimulates IL-6 production in osteoblasts by a mechanism likely to be mediated by VPAC2 receptors and dependent on cyclic AMP/protein kinase A/CREB activation and also involving the transcription factors C/EBP and AP-1.

  • 16. Swanberg, Maria
    et al.
    McGuigan, Fiona
    Ivaska, Kaisa K
    Gerdhem, Paul
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Bucala, Richard
    Kuchel, George
    Kenny, Anne
    Akesson, Kristina
    Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women2010In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 47, no 2, p. 424-429Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far. Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated with inflammatory disorders such as rheumatoid arthritis. We investigated the association of polymorphisms in the MIF gene with bone mineral density (BMD) and bone loss in 1002 elderly women using MIF promoter polymorphisms MIF-CATT(5-8) and rs755622(G/C) located -794 and -173 bp upstream of the transcriptional start site. Bone loss was estimated both by the change in BMD over 5 years and by the levels of bone resorption markers in serum measured at four occasions during a 5-year period. The MIF-CATT(7)/rs755622(C) haplotype was associated with increased rate of bone loss during 5 years at the femoral neck (p<0.05) and total hip (p<0.05). In addition, the MIF-CATT(7)/rs755622(C) haplotype carriers had higher levels of the bone turnover marker serum C-terminal cross-linking telopeptide of type I collagen (S-CTX-I, p<0.01) during the 5 year follow-up period. There was no association between MIF-CATT(7)/rs755622(C) and baseline BMD at femoral neck, total hip or lumbar spine. We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women.

  • 17.
    Tervo, Taru
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Neovius, Martin
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute (Solna), Stockholm, Sweden.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Reduced physical activity corresponds with greater bone loss at the trabecular than the cortical bone sites in men2009In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 45, no 6, p. 1073-1078Article in journal (Refereed)
    Abstract [en]

    Previous research has been inconclusive as to whether high peak bone mineral density (BMD, g/cm(2)) resulting from previous physical activity is retained with reduced activity later in life. The aim of this 12-year longitudinal study was to investigate the association between BMD loss and reduced physical activity (h/wk) at trabecular and cortical bone sites in men. Three groups with a mean age of 17 years at baseline were investigated: i) 51 athletes who discontinued their active careers during the follow-up period (former athletes), ii) 16 athletes who were active throughout the follow-up period (active athletes), and iii) 25 controls. BMD loss at the hip, spine, and pelvis (mainly trabecular bone) was compared to BMD loss at femur, humerus, and legs (mainly cortical bone) during a 12-year follow-up period. Across the total follow-up period in the total cohort, reduced physical activity was more strongly associated with changes at trabecular BMD sites, i.e. hip, spine, and pelvis (B=0.008-0.005 g/cm(2) per weekly hour physical activity (h), p<0.001), than at cortical bone sites, i.e. humerus, legs (B=0.002-0.003 g/cm(2)/h, p<0.05), and femur (p>0.05). At the final follow-up, former athletes showed higher BMD than controls only at the cortical bone sites of the humerus, legs, and femur (difference 0.05-0.10 g/cm(2), p<0.05). In conclusion, this study indicates that predominantly trabecular bone is lost with reduced physical activity levels in young men. Benefits were still evident at the more cortical sites eight years after the discontinuation of an active sports career.

  • 18.
    Tervo, Taru
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Effects of badminton and ice hockey on bone mass in young males: a 12-year follow-up.2010In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 47, no 3, p. 666-72Article in journal (Refereed)
    Abstract [en]

    The purpose of the present study was to investigate the influence of different types of weight bearing physical activity on bone mineral density (BMD, g/cm(2)) and evaluate any residual benefits after the active sports career. Beginning at 17 years of age, BMD was measured 5 times, during 12 years, in 19 badminton players, 48 ice hockey players, and 25 controls. During the active career, badminton players gained significantly more BMD compared to ice hockey players at all sites: in their femoral neck (mean difference (Delta) 0.06 g/cm(2), p=0.04), humerus (Delta 0.06 g/cm(2), p=0.01), lumbar spine (Delta 0.08 g/cm(2), p=0.01), and their legs (Delta 0.05 g/cm(2), p=0.003), after adjusting for age at baseline, changes in weight, height, and active years. BMD gains in badminton players were higher also compared to in controls at all sites (Delta 0.06-0.17 g/cm(2), p<0.01 for all). Eleven badminton players and 37 ice hockey players stopped their active career a mean of 6 years before the final follow-up. Both these groups lost significantly more BMD at the femoral neck and lumbar spine compared to the control group (Delta 0.05-0.12 g/cm(2), p<0.05 for all). At the final follow-up, badminton players had significantly higher BMD of the femoral neck, humerus, lumbar spine, and legs (Delta 0.08-0.20 g/cm(2), p<0.01 for all) than both ice hockey players and controls. In summary, the present study may suggest that badminton is a more osteogenic sport compared to ice hockey. The BMD benefits from previous training were partially sustained with reduced activity.

  • 19. van der Eerden, B. C. J.
    et al.
    Oei, L.
    Roschger, P.
    Fratzl-Zelman, N.
    Hoenderop, J. G. J.
    van Schoor, N. M.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Schreuders-Koedam, M.
    Uitterlinden, A. G.
    Hofman, A.
    Suzuki, M.
    Klaushofer, K.
    Ohlsson, C.
    Lips, P. J. A.
    Rivadeneira, F.
    Bindels, R. J. M.
    van Leeuwen, J. P. T. M.
    TRPV4 deficiency causes sexual dimorphism in bone metabolism and osteoporotic fracture risk2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 57, no 2, p. 443-454Article in journal (Refereed)
    Abstract [en]

    We explored the role of transient receptor potential vanilloid 4 (TRPV4) in murine bone metabolism and association of TRPV4 gene variants with fractures in humans. Urinary and histomorphometrical analyses demonstrated reduced osteoclast activity and numbers in male Trpv4(-/-) mice, which was confirmed in bone marrow-derived osteoclast cultures. Osteoblasts and bone formation as shown by serum procollagen type 1 amino-terminal propeptide and histomorphometry, including osteoid surface, osteoblast and osteocyte numbers were not affected in vivo. Nevertheless, osteoblast differentiation was enhanced in Trpv4(-/-) bone marrow cultures. Cortical and trabecular bone mass was 20% increased in male Trpv4(-/-) mice, compared to sex-matched wild type (Trpv4(+/+)) mice. However, at the same time intracortical porosity was increased and bone matrix mineralization was reduced. Together, these lead to a maximum load, stiffness and work to failure of the femoral bone, which were not different compared to Trpv4(+/+) mice, while the bone material was less resistant to stress and less elastic. The differential impacts on these determinants of bone strength were likely responsible for the lack of any changes in whole bone strength in the Trpv4(-/-) mice. None of these skeletal parameters were affected in female Trpv4(-/-) mice. The T-allele of rs1861809 SNP in the TRPV4 locus was associated with a 30% increased risk (95% Cl: 1.1-1.6; p = 0.013) for non-vertebral fracture risk in men, but not in women, in the Rotterdam Study. Meta-analyses with the population-based LASA study confirmed the association with non-vertebral fractures in men. This was lost when the non-population-based studies Mr. OS and UFO were included. In conclusion, TRPV4 is a male-specific regulator of bone metabolism, a determinant of bone strength, and a potential risk predictor for fractures through regulation of bone matrix mineralization and intra-cortical porosity. This identifies TRPV4 as a unique sexually dimorphic therapeutic and/or diagnostic candidate for osteoporosis.

  • 20. Zheng, H. -F
    et al.
    Duncan, E.
    Eriksson, J.
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Yerges-Armstrong, L.
    Leo, P.
    Vandenput, L.
    Nicholson, G.
    Ladouceur, M.
    Prince, R.
    Leslie, W.
    Eisman, J.
    Goltzman, D.
    Jones, G.
    Xiao, Y.
    Liu, J.
    Reid, I.
    Sambrook, P.
    Dennison, E.
    Danoy, P.
    Wilson, S.
    McCloskey, E.
    Eastell, R.
    Spector, T.
    Mitchell, B.
    Streeten, E.
    Brommage, R.
    Lorentzon, M.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Brown, M.
    Ohlsson, C.
    Richards, J. B.
    The 7Q31 locus, containing WNT16, is associated with bone mineral density, osteoporotic fracture and bone strength2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S33-S34Article in journal (Refereed)
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