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  • 1.
    Behnam-Mothlag, Parviz
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Tyler, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Cisplatin Resistance in Malignant Pleural Mesothelioma2012Inngår i: Mesotheliomas: Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis / [ed] Alexander Zubritsky, Zagreb: InTech, 2012, Vol. 11, 169-186 s.Kapittel i bok, del av antologi (Fagfellevurdert)
  • 2. Belibasakis, Georgios N
    et al.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes2012Inngår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 59, nr 1, 124-130 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Periodontitis is an inflammatory condition that destroys the tooth-supporting tissues, as a result of local bacterial infection. Aggregatibacter actinomycetemcomitans is a Gram-negative facultative anaerobic species, highly associated with aggressive periodontitis. Periodontal inflammation is dominated by cytokines of the Interleukin (IL)-1 family. Prior to their secretion by mononuclear cells, IL-1 cytokines are processed by intracellular protein complexes, known as "inflammasomes", which can sense the bacterial challenge. The aim of this study was to investigate which inflammasomes are regulated in mononuclear cells in response to A. actinomycetemcomitans. The D7SS strain and its derivative leukotoxin and cytolethal distending toxin knock-out mutant strains were used to infect human mononuclear cells at a 1:10 cell: bacteria ratio, for 3h. The expression of various inflammasome components in the cells was investigated by TaqMan quantitative real-time polymerase chain reaction (qPCR). The expressions of NOD-like receptor protein (NLRP)1, NLRP2 and Absent In Melanoma (AIM)2 inflammasome sensors, as well as their effector Caspase-1 were not affected. However, NLRP3 was up-regulated, while NLRP6 was down-regulated. This effect was not dependent on the leukotoxin or the cytolethal distending toxin, as demonstrated by the use of specific gene knock-out mutant strains. IL-1β and IL-18 expressions were also up-regulated by the bacterial challenge. In conclusion, A. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation.

  • 3. Bougas, Kostas
    et al.
    Ransjö, Maria
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Effects of Porphyromonas gingivalis surface-associated material on osteoclast formation2013Inngår i: Odontology: official journal of The Society of the Nippon Dental University, ISSN 1618-1247, E-ISSN 1618-1255, Vol. 101, nr 2, 141-149 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Porphyromonas gingivalis strongly correlates with periodontitis, but the underlying mechanisms causing dentoalveolar bone resorption are not fully understood. As contradictory effects of P. gingivalis on osteoclastogenesis have been reported, this study investigates the effect of P. gingivalis extract on osteoclast formation. Osteoclast formation in mouse bone marrow (MBM) cell cultures and RAW 264.7 cells was stimulated by nuclear factor-κB ligand (RANKL) or parathyroid hormone (PTH). Cells were cultured with and without P. gingivalis surface-associated material and phenotypic characteristics were examined using microscopy, flow cytometry, and RT-PCR. P. gingivalis significantly decreased osteoclast formation and the expression of osteoclast phenotypic markers in PTH-stimulated MBM cultures. Additionally, P. gingivalis inhibited expression of osteoclast differentiation factors and stimulated expression of the mouse macrophage marker F4/80. The presence of P. gingivalis in RANKL-stimulated MBM cultures and RAW 264.7 cells inhibited osteoclastogenesis. Interestingly, a transient exposure with P. gingivalis before PTH stimulation increased osteoclastogenesis in MBM cultures. Flow cytometric analyses of cells transiently exposed to P. gingivalis demonstrated an increased proportion of potential osteoclast precursor cells. We conclude that a transient exposure of MBM cultures to P. gingivalis increases the number of osteoclast precursors and osteoclast formation, whereas a prolonged exposure completely abolishes osteoclastogenesis.

  • 4.
    Conaway, H Herschel
    et al.
    University of Arkansas for Medical Sciences.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Retinoids and bone2011Inngår i: Contemporary aspects of endocrinology / [ed] Evanthia Diamanti-Kandarakis, InTech, 2011, 443-454 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 5.
    Conaway, H. Herschel
    et al.
    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
    Pirhayati, Amir
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Persson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Pettersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Svensson, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Lindholm, Catharina
    Center for Bone and Arthritis Research at the Institute for Medicine, Sahlgrenska Academy at the University of Gothenburg.
    Henning, Petra
    Center for Bone and Arthritis Research at the Institute for Medicine, Sahlgrenska Academy at the University of Gothenburg.
    Tuckermann, Jan
    Tissue-specific Hormone Action, Leibniz Institute for Age Research, Fritz Lipmann Institute, D-07745 Jena, Germany.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL: a Response Inhibited by Monomeric Glucocorticoid Receptor2011Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, 31425-31436 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of (45)Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of (45)Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RAR alpha/beta/gamma) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RAR alpha enhanced the release of (45)Ca and mRNA expression of Rankl, whereas agonists with affinity to RAR beta/gamma or RAR gamma had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RAR alpha antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on 45Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR(dim) mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RAR alpha receptors, a response that can be inhibited by monomeric GR.

  • 6.
    Granholm, Susanne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Henning, Petra
    Göteborgs universitet.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Comparisons between the effects of calcitonin receptor-stimulating peptide and intermedin and other peptides in the calcitonin family on bone resorption and osteoclastogenesis2011Inngår i: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 112, nr 11, 3300-3312 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Calcitonin receptor-stimulating peptide (CRSP) and intermedin (IMD) are two recently discovered peptides in the calcitonin (CT) family of peptides. CRSP and IMD, similar to CT, calcitonin gene-related peptide (CGRP) and amylin (AMY), but in contrast to adrenomedullin (ADM), inhibited bone resorption in mouse calvarial bones. CRSP and IMD, similar to CT, CGRP, AMY, but in contrast to ADM, decreased formation of osteoclasts and number of pits in bone marrow macrophage cultures stimulated by M-CSF and RANKL, with no effect on the expression of a number of genes associated with osteoclast progenitor cell differentiation. CRSP and IMD inhibited osteoclastogenesis at a late stage but had no effect on DC-STAMP mRNA. IMD, similar to CGRP, AMY and ADM stimulated cyclic AMP formation in M-CSF expanded osteoclast progenitor cells lacking CT receptors. RANKL induced CT receptors and a cyclic AMP response also to CT and CRSP, and increased the cyclic AMP response to CGRP, AMY and IMD but decreased the response to ADM. Our data demonstrate that CRSP and IMD share several functional properties of peptides in the CT family of peptides, including inhibition of bone resorption and osteoclast formation. The data also show that the reason why ADM does not inhibit osteoclast activity or formation is related to the fact that RANKL decreases ADM receptor signalling through the adenylate cyclase-cyclic AMP pathway. Finally, the findings indicate that activation by CGRP, AMY and IMD may include activation of both CT and CT receptor-like receptors. J. Cell. Biochem. © 2011 Wiley-Liss, Inc.

  • 7. Henning, P.
    et al.
    Kindlund, B.
    Pettersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Conaway, H. H.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Inhibition of osteoclast formation in human peripheral CD14+cells by vitamin A2012Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, nr Supplement 1, S92-S92 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 8. Henningsson, Louise
    et al.
    Jirholt, Pernilla
    Bogestal, Yalda Rahpeymai
    Eneljung, Tove
    Adiels, Martin
    Lindholm, Catharina
    McInnes, Iain
    Bulfone-Paus, Silvia
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Gjertsson, Inger
    Interleukin 15 mediates joint destruction in staphylococcus aureus arthritis2012Inngår i: Journal of Infectious Diseases, ISSN 0022-1899, Vol. 206, nr 5, 687-696 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Staphylococcus aureus arthritis causes severe and rapid joint damage despite antibiotics. Thus, there is a need to identify new treatment targets in addition to antibiotics. Lately, interleukin 15 (IL-15) has been implicated both in osteoclastogenesis and in bacterial clearance-2 important issues in S. aureus-induced joint destruction. This has prompted us to investigate the importance of IL-15 in S. aureus-induced arthritis.

    Methods.Toxic shock syndrome toxin-1 producing S. aureus was intravenously inoculated in IL-15 knockout and wildtype mice and in wildtype mice treated with anti-IL-15 antibodies (aIL-15ab) or isotype control antibody.

    Results. Absence of IL-15, either in knockout mice or after treatment with aIL-15ab, significantly reduced weight loss compared with controls during the infection. The severity of synovitis and joint destruction was significantly decreased in IL-15 knockout and aIL-15ab treated mice compared with controls. In IL-15 knockout mice there was a reduced number of osteoclasts in the joints. The host's ability to clear bacteria was not influenced in the IL-15 knockout mice, but significantly increased after treatment with aIL-15ab.

    Conclusions. IL-15 is a mediator of joint destruction in S. aureus-induced arthritis and contributes to general morbidity, which makes this cytokine an interesting treatment target in addition to conventional antibiotics.

  • 9.
    Höglund Åberg, Carola
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Antonoglou, Georgios
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Haubek, Dorte
    Section for Pediatric Dentistry, Department of Dentistry, Health, Århus University, Århus, Denmark.
    Kwamin, Francis
    Dental School University of Ghana, Accra, Ghana.
    Claesson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression 2013Inngår i: PLoS ONE, ISSN 1932-6203, Vol. 8, nr 6, e65781- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Objectives: The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt-activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL).

    Material and Methods: A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up.

    Results: Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt-activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR = 5.126; 95% CI = [2.994 - 8.779], p < 0.001).

    Conclusion: A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt-genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity.

  • 10.
    Höglund Åberg, Carola
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Kwamin, Francis
    Univ Ghana, Sch Dent, Accra, Ghana.
    Claesson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Oral mikrobiologi.
    Haubek, Dorte
    Århus Univ, Dept Dent, Århus, Denmark.
    Presence of JP2 and Non-JP2 genotypes of aggregatibacter actinomycetemcomitans and periodontal attachment loss in adolescents in Ghana2012Inngår i: Journal of Periodontology, ISSN 0022-3492, Vol. 83, nr 12, 1520-1528 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Limited data are reported concerning the presence of A. actinomycetemcomitans and attachment loss (AL) in sub-Saharan countries. The authors investigate the carrier frequency of JP2 and non-JP2 genotypes of A. actinomycetemcomitans and the presence of AL in Ghanaian adolescents and evaluate socioeconomic conditions and oral hygiene practices. Methods: Five hundred individuals (mean +/- SD age: 13.2 +/- 1.5 years) in public and private schools were interviewed about demographic characteristics and oral hygiene practices and were given a full-mouth periodontal examination. Subgingival plaque samples were obtained from periodontal sites around permanent first molars and incisors. The carrier status of A. actinomycetemcomitans at the individual level was determined based on results obtained by cultivation and polymerase chain reaction. Results: The findings of this study show a relatively high carrier rate of JP2 and non-JP2 genotypes of Aggregatibacter actinomycetemcomitans in the Ghanaian adolescent population and the presence of this bacterium is associated with the occurrence of AL. The overall carrier rate of A. actinomycetemcomitans was 54.4%, and the highly leukotoxic JP2 genotype was detected in 8.8% of the study population. A total of 107 (21.4%) individuals had >= 1 tooth with AL >= 3 mm. The majority of the individuals carrying A. actinomycetemcomitans (80.1%) (P<0.001) and of the periodontally diseased individuals (91.6%) (P<0.001) were found in public schools. Conclusions: A. actinomycetemcomitans and AL were frequently found in Ghanaian adolescents. The school type was the strongest predictor of both presence of A. actinomycetemcomitans and AL.

  • 11.
    Johansson, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Eriksson, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Åhren, Ann-Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Boman, Kurt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Prevalence of systemic immunoreactivity to Aggregatibacter actinomycetemcomitans leukotoxin in relation to the incidence of myocardial infarction2011Inngår i: BMC Infectious Diseases, ISSN 1471-2334, Vol. 11, nr 1, 55- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular disease (CVD). The proinflammatory cytokine, interleukin (IL)-1, is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Aggregatibacter actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1 from macrophages. The aim of the present study was to compare the prevalence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin in myocardial infarction (MI) cases (n=532) and matched controls (n=1000) in a population-based case and referents study in northern Sweden.

    Methods: Capacity to neutralize A. actinomycetemcomitans leukotoxin was analyzed in a bioassay with leukocytes, purified leukotoxin, and plasma. Plasma samples that inhibited lactate-dehydrogenase release from leukotoxin-lysed cells by 50 % were classified as positive.

    Results: Neutralizing capacity against A. actinomycetemcomitans leukotoxin was detected in 53.3% of the plasma samples. The ability to neutralize leukotoxin correlated to increasing age in men (n=1082) but not in women (n=450). There was no correlation between presence of systemic leukotoxin neutralization capacity and the incidence of MI, except for women (n=146). Women with a low neutralizing capacity had a significantly higher incidence of MI than those who had a high neutralizing capacity.

    Conclusions: Systemic immunoreactivity against A. actinomycetemcomitans leukotoxin was found at a high prevalence in the analyzed population of adults from northern Sweden. The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI.

  • 12.
    Johansson, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Kalfas, Sotos
    Aristotle University, Thessaloniki, Greece.
    Virulence Mechanisms of Leukotoxin from Aggregatibacter actinomycetemcomitans2012Inngår i: Oral Health Care: Prosthodontics, Periodontology, Biology, Research and Systemic Conditions / [ed] Mandeep Singh Virdi, Zagreb: InTech, 2012, 165-192 s.Kapittel i bok, del av antologi (Fagfellevurdert)
  • 13. Johansson, H.
    et al.
    Oden, A.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Jutberger, H.
    Lorentzon, M.
    Barrett-Connor, E.
    Karlsson, M. K.
    Ljunggren, O.
    Smith, U.
    McCloskey, E.
    Kanis, J. A.
    Ohlsson, C.
    Mellstrom, D.
    High serum adiponectin predicts incident fractures in elderly men: mr os sweden2012Inngår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 23, nr Suppl 2, S306-S307 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 14. Johansson, Helena
    et al.
    Oden, Anders
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Jutberger, Hans
    Lorentzon, Mattias
    Barrett-Connor, Elizabeth
    Karlsson, Magnus K
    Ljunggren, Östen
    Smith, Ulf
    McCloskey, Eugene
    Kanis, John A
    Ohlsson, Claes
    Mellström, Dan
    High serum adiponectin predicts incident fractures in elderly men: osteoporotic fractures in men (MrOS) Sweden2012Inngår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, nr 6, 1390-1396 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adipocytes and osteoblasts share a common progenitor, and there is, therefore, potential for both autocrine and endocrine effects of adiponectin on skeletal metabolism. The aim of the present study was to determine whether high serum adiponectin was associated with an increased risk of fracture in elderly men. We studied the relationship between serum adiponectin and the risk of fracture in 999 elderly men drawn from the general population and recruited to the Osteoporotic Fractures in Men (MrOS) study in Gothenburg, Sweden. Baseline data included general health questionnaires, lifestyle questionnaires, body mass index (BMI), bone mineral density (BMD), serum adiponectin, osteocalcin, and leptin. Men were followed for up to 7.4 years (average, 5.2 years). Poisson regression was used to investigate the relationship between serum adiponectin, other risk variables and the time-to-event hazard function of fracture. Median levels of serum adiponectin at baseline were 10.4 mu g/mL (interquartile range, 7.714.3). During follow-up, 150 men sustained one or more fractures. The risk of fracture increased in parallel with increasing serum adiponectin (hazard ratio [HR]/SD, 1.46; 95% confidence interval [CI], 1.231.72) and persisted after multivariate-adjusted analysis (HR/SD, 1.30; 95% CI, 1.091.55). Serum adiponectin shows graded stepwise association with a significant excess risk of fracture in elderly men that was independent of several other risk factors for fracture. Its measurement holds promise as a risk factor for fracture in men. (C) 2012 American Society for Bone and Mineral Research.

  • 15.
    Kassem, Ali
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lunberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lindholm, C.
    Souza, P.
    Lerner, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Regulation of osteoclast formation by toll-like receptors 2 and 52012Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, nr Supplement 1, S86-S87 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 16.
    Kassem, Ali
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lunberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lindholm, C.
    Souza, P.
    Lerner, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Regulation of osteoclast formation by toll-like receptors 2 and 52012Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, nr Supplement 1, S67-S67 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 17.
    Kassem, Ali
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Souza, Pedro C. C.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Stimulation of bone resorption in calvarial bones by toll-like2 receptor through enhanced rankl2012Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, A68-A68 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 18.
    Koskinen, Cecilia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Persson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Baldock, P.
    Garvan Institute of Medical Research, Darlinghurst, New South Wales.
    Oldenborg, Per-Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lack of CD47 leads to impaired bone cell differentiation and results in an osteopenic bone phenotype2012Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, nr Supplement 1, S42-S43 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 19. Kwamin, Francis
    et al.
    Gref, Rolf
    Haubek, Dorte
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Interactions of extracts from selected chewing stick sources with Aggregatibacter actinomycetemcomitans2012Inngår i: BMC Research Notes, ISSN 1756-0500, Vol. 5, 203- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Aggregatibacter actinomycetemcomitans produces a leukotoxin that activates a pro-inflammatory death of human monocytes/macrophages. A specific clone of this bacterium (JP2) has a 530-base pair deletion in the leukotoxin promoter gene that causes a significantly enhanced expression of leukotoxin. This specific clone of A. actinomycetemcomitans is common in some African populations and has a strong association with periodontal attachment loss in adolescents in these populations. Chewing sticks of plant origin are commonly used as oral hygiene tool in Africa, but their role as a therapeutic agent in periodontal disease is poorly investigated. RESULTS: Ethanol extracts were made from 7 common plants used as chewing sticks in West-Africa. None of the tested extracts inhibited growth of A. actinomycetemcomitans. However, extracts from Psidium guajava (Guava) completely neutralized the cell death and pro-inflammatory response of human leukocytes induced by the leukotoxin. None of the six other tested chewing stick extracts showed this effect. CONCLUSIONS: The discovery that extracts from Guava efficiently neutralizes A. actinomycetemcomitans leukotoxicity might lead to novel therapeutic agents and strategies for prevention and treatment of aggressive forms of periodontitis induced by infections with the highly leukotoxic JP2 clone of this bacterium.

  • 20.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Skelettet i käkar och annorstädes: 4. Skelettet som ett hormonproducerande organ med betydelse för energimetabolism och fosfatutsöndring2012Inngår i: Tandläkartidningen, ISSN 0039-6982, Vol. 104, nr 8, 60-68 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Ny forskning visar att skelettet inte bara regleras av hormoner utan också producerar hormoner. Dessa hormoner påverkar fettceller, insulinproducerande celler i bukspottkörteln och njurens fosfatreglering.

  • 21.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Vad gör A-vitaminen med skelettet?2010Inngår i: Osteoporos-nytt, ISSN 1404-6199, nr 4, 10-11 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 22.
    Lerner, Ulf H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Brechter, Anna
    Palmqvist, Py
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Persson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Skelettet vid hälsa och sjukdom2008Inngår i: Tandläkartidningen, ISSN 0039-6982, Vol. 100, nr 5, 84-90 s.Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [sv]

    Hur ombyggnaden av benvävnaden i käkar och skelett fungerar och hur processen påverkas vid sjukdomstillstånd som parodontit, benskörhet, tumörer med mera är föremål för omfattande forskning i Umeå.

  • 23.
    Lerner, Ulf H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Mellström, Dan
    Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Behandlingsprinciper för olika läkemedel vid osteoporos: skelettet i käkar och annorstädes, del 52012Inngår i: Tandläkartidningen, ISSN 0039-6982, Vol. 104, nr 11, 64-79 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Osteoporos drabbar många individer i hela världen. Från att ha varit en sjukdom utan farmakologisk behandling har ett flertal läkemedel nu utvecklats och fler är på väg. Här beskrivs behandlingsprinciperna för de läkemedel som i dag används vid osteoporos.

  • 24.
    Lerner, Ulf H
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Ohlsson, Claes
    Ahlman, Håkan
    Mellström, Dan
    Serotonin: budbärare mellan hjärna/tunntarm och skelett. Djurmodeller styrker hypotes om serotoninets roll för bildning av benmassa2011Inngår i: Läkartidningen, ISSN 0023-7205, Vol. 108, nr 11, 600-605 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies by Karsenty and co-workers at Columbia University, New York, have demonstrated the importance in skeletal remodeling in mice of serotonin in the brain and in the periphery. Leptin activates receptors in the brain stem which inhibit tryptophane hydroxylase 2 (Tph2), decreasing serotonin biosynthesis. As a consequence, fewer hypothalamic serotonin receptors are activated, sympathetic outflow increases, and there is enhanced activation of ?-adrenergic receptors on osteoblasts. This leads to decreased bone formation, and increased expression of RANKL, which stimulates bone resorption. In contrast, peripheral serotonin is produced in enterochromaffine cells in the dudenum by the enzyme Tph1. Activation of osteoblastic receptors by peripheral serotonin decreases bone formation without affecting RANKL or resorption. Interstingly, pharmacological inhibition of Tph1 in the duodenum can prevent bone loss after ovariectomy in both mice and rats. These preclinical data need to be confirmed in humans and the feedback loops between the skeleton and serontonin releasing cells in brain and gut to be elucidated.

  • 25.
    Mladenovic, Zivko
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Sahlin-Platt, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Ortodonti.
    Andersson, Britta
    Department of Medicine Solna, Karolinska Institutet, S-171 76 Stockholm,Sweden.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Björn, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    In vitro study of the biological interface of Bio-Oss: implications of the experimental setup2013Inngår i: Clinical Oral Implants Research, ISSN 0905-7161, E-ISSN 1600-0501, Vol. 24, nr 3, 329-335 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives To systematically investigate the biological interface of Bio-Oss by analysing dissolution–precipitation behaviour and osteogenic responses using in vitro experimental systems.

    Material and methods Different concentrations (1–100 mg/ml) of Bio-Oss were incubated in cell culture medium for 24 h before elemental concentrations for calcium, phosphorus and silicon in the medium were analysed with inductive coupled plasma-optical emission spectroscopy. Radioactive calcium-45 isotope labelling technique was used to study possible precipitation of calcium on the Bio-Oss particle. Biological interface of Bio-Oss was studied in osteogenic experiments using mineralization medium and three different sources of cells (primary mouse bone marrow stromal cells, primary rat calvarial cells and MC3T3-E1 mouse pre-osteoblast cell line). Cells were fixed and stained with Toulidine blue, von Kossa or Alizarin Red staining for confirmation of extracellular matrix mineralization.

    Results Elemental analysis of the cell culture medium demonstrated a significant decrease of calcium and phosphorus and a dose-dependent release of silicon to the medium after incubation with Bio-Oss. A significant decrease of calcium and phosphorus in the medium occurred even at low concentrations of Bio-Oss. Uptake of calcium on the Bio-Oss particle was confirmed with radioactive calcium-45 isotope labelling technique. In osteogenic experiments with Bio-Oss (<1 mg/ml), matrix mineralization around the Bio-Oss particles were demonstrated in all three cell types with von Kossa and Alizarin Red staining.

    Conclusion Dissolution–precipitation reactions occur at the surface of Bio-Oss, and osteogenic responses are seen at the biological interface. The concentration of Bio-Oss is a key factor for the experimental in vitro results, and may also have implications for the clinic.

  • 26.
    Persson, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    The neuropeptide VIP regulates the expression of osteoclastogenic factors in osteoblasts2011Inngår i: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 112, nr 12, 3732-3741 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Osteoclast formation is controlled by stromal cells/osteoblasts expressing macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), crucial for osteoclast progenitor cell proliferation, survival and differentiation, and osteoprotegerin (OPG) that inhibits the interaction between RANKL and its receptor RANK. Recent data have strongly indicated that the nervous system play an important role in bone biology. In the present study, the effects of the neuropeptide vasoactive intestinal peptide (VIP), present in peptidergic skeletal nerve fibers, on the expression of RANKL, OPG, and M-CSF in osteoblasts and stromal cells have been investigated. VIP and pituitary adenylate cyclase-activating polypeptide 38 (PACAP-38), but not secretin, stimulated rankl mRNA expression in mouse calvarial osteoblasts. In contrast, VIP inhibited the mRNA expressions of opg and m-csf, effects shared by PACAP-38, but not by secretin. VIP did not affect rankl, opg or m-csf mRNA expression in mouse bone marrow stromal cells. The effects by VIP on the mRNA expression of rankl, opg and m-csf were all potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram. In addition, VIP robustly enhanced the phosphorylation of ERK and the stimulatory effect by VIP on rankl mRNA was inhibited by the MEK1/2 inhibitor PD98059. These observations demonstrate that activation of VPAC(2) receptors in osteoblasts enhances the RANKL/OPG ratio by mechanisms mediated by cyclic AMP and ERK pathways suggesting an important role for VIP in bone remodelling. J. Cell. Biochem. © 2011 Wiley-Liss, Inc.

  • 27.
    Remen, Kirsten M Robertson
    et al.
    Karolinska institutet.
    Henning, Petra
    Göteborgs universitet.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Gustafsson, Jan-Åke
    Karolinska institutet.
    Andersson, Göran
    Karolinska institutet.
    Activation of Liver X Receptor (LXR) Inhibits Receptor Activator of Nuclear Factor {kappa}B Ligand (RANKL)-induced Osteoclast Differentiation in an LXR{beta}-dependent Mechanism.2011Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, nr 38, 33084-94 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bone destruction is the major pathological process in many bone metabolic diseases and is a result of increased osteoclast formation and bone resorption. The liver X receptors (α,β), important regulators of cholesterol metabolism and inflammatory signaling, have recently been observed to play a role in both physiological and pathological bone turnover. However, the relationship between liver X receptors (LXR) and osteoclast differentiation/formation remains unknown. Here, we report that the LXR ligand GW3965 is able to clearly and potently inhibit the formation of mature osteoclasts from receptor activator of nuclear factor κB ligand (RANKL)-stimulated human and murine osteoclast precursors. This results in a significant inhibition of bone resorption. We observed that GW3965 significantly inhibited expression of the osteoclast markers tartrate-resistant acid phosphatase, cathepsin K, osteoclast-associated receptor (OSCAR), and calcitonin receptor, appearing to act in an NFATc1/p38/microphthalmia-associated transcription factor (MITF)-dependent mechanism, independently of receptor activator of nuclear factor κB or c-Fos and not directly involving the NFκB pathways. GW3965 was less effective in RAW264.7 monocyte/macrophage cells, which are more committed into the osteoclast lineage. Also, GW3965 seemed to act differently depending on the source of the progenitor cells as it had no effect on calvarial osteoclasts, compared with marrow or blood-derived monocytes. As these effects were abolished in osteoclast precursors derived from LXRβ(-/-) mice, we suggest that GW3965 acts via an LXRβ-dependent mechanism. Taken together, our results suggest that the LXR can act as an important inhibitor of RANKL-mediated osteoclast differentiation.

  • 28. Sjögren, Klara
    et al.
    Engdahl, Cecilia
    Henning, Petra
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Tremaroli, Valentina
    Lagerquist, Marie K
    Backhed, Fredrik
    Ohlsson, Claes
    The gut microbiota regulates bone mass in mice2012Inngår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, nr 6, 1357-1367 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The gut microbiota modulates host metabolism and development of immune status. Here we show that the gut microbiota is also a major regulator of bone mass in mice. Germ-free (GF) mice exhibit increased bone mass associated with reduced number of osteoclasts per bone surface compared with conventionally raised (CONV-R) mice. Colonization of GF mice with a normal gut microbiota normalizes bone mass. Furthermore, GF mice have decreased frequency of CD4+ T cells and CD11b+/GR 1 osteoclast precursor cells in bone marrow, which could be normalized by colonization. GF mice exhibited reduced expression of inflammatory cytokines in bone and bone marrow compared with CONV-R mice. In summary, the gut microbiota regulates bone mass in mice, and we provide evidence for a mechanism involving altered immune status in bone and thereby affected osteoclast-mediated bone resorption. Further studies are required to evaluate the gut microbiota as a novel therapeutic target for osteoporosis. (C) 2012 American Society for Bone and Mineral Research.

  • 29.
    Souza, Pedro P. C.
    et al.
    Department of Physiology and Pathology, Araraquara School of Dentistry, Univ. Estadual Paulista – UNESP, Araraquara, Brazil.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg.
    The role of cytokines in inflammatory bone loss2013Inngår i: Immunological Investigations, ISSN 0882-0139, Vol. 42, nr 7, 555-622 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic inflammatory processes close to bone often lead to loss of bone in diseases such as rheumatoid arthritis, periodontitis, loosened joint prosthesis and tooth implants. This is mainly due to local formation of bone resorbing osteoclasts which degrade bone without any subsequent coupling to new bone formation. Crucial for osteoclastogenesis is stimulation of mononuclear osteoclast progenitors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL) which induces their differentiation along the osteoclastic lineage and the fusion to mature, multinucleated osteoclasts. M-CSF and RANKL are produced by osteoblasts/osteocytes and by synovial and periodontal fibroblasts and the expression is regulated by pro-and anti-inflammatory cytokines. These cytokines also regulate osteoclastic differentiation by direct effects on the progenitor cells. In the present overview, we introduce the basic concepts of osteoclast progenitor cell differentiation and summarize the current knowledge on cytokines stimulating and inhibiting osteoclastogenesis by direct and indirect mechanisms.

  • 30.
    Souza, Pedro P. C.
    et al.
    Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University, Araraquara, Brazil.
    Palmqvist, Py
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Lundgren, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Hänström, Lennart
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Souza, Joao A. C.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Conaway, H. Herschel
    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Interleukin-4 and interleukin-13 inhibit the expression of leukemia inhibitory factor and interleukin-11 in fibroblasts2012Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 49, nr 4, 601-610 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cytokines produced by inflammatory or resident mesenchymal cells play important modulatory roles in the pathogenesis of inflammation induced bone loss. In the present study, the effects of IL-4 and IL-13 on the expression of three osteotropic cytokines in the IL-6 family expressed in human gingival fibroblasts were studied. IL-4R alpha and IL-13R alpha 1 mRNA were constitutively expressed in human gingival fibroblasts. The inflammatory cytokines IL-1 beta and TNF-alpha increased expression of IL-5, LIF, and IL-11 mRNA and protein in the gingival fibroblasts. Addition of IL-4 or IL-13 had no effect on IL-6 expression, but significantly inhibited LIF and IL-11 mRNA and protein stimulated by IL-1 beta and TNF-alpha. No involvement of NF-kappa B or STAT1 was observed in the inhibition. STAT6 was phosphorylated at Y641 by treatment with IL-4 and knockdown of STAT6 with siRNA decreased the inhibition of IL-11 and LIF expression by IL-4 in IL-1 beta and TNF-alpha stimulated cells. This study suggests that activation of STAT6 by IL-4 and IL-13, through type 2 IL-4 receptors, inhibits production of IL-11 and LIF stimulated by IL-1 beta and TNF-alpha in human gingival fibroblasts. A negative modulatory role of IL-4 and IL-13 in osteotropic cytokine production could be a mechanism playing an important inhibitory role in inflammation induced periodontitis. (C) 2011 Elsevier Ltd. All rights reserved.

  • 31.
    Strålberg, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Henning, P.
    Gjertson, I
    Kindlund, B.
    Souza, P. P. C.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Persson, Emelie
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Abrahamson, M.
    Kasprzykowski, F.
    Grubb, A.
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Cysteine proteinase inhibitors decrease rankl and lps induced differentiation of human and mouse osteoclast progenitor cells2012Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, A70-A70 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 32.
    Strålberg, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Henning, Petra
    Gjertsson, Inger
    Kindlund, Bert
    Souza, Pedro PC
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Persson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Abrahamson, Magnus
    Kasprzykowski, Franciszek
    Grubb, Anders
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi. Göteborgs universitet.
    Cysteine proteinase inhibitors regulate human and mouse osteoclastogenesis by interfering with RANK signaling2013Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr 7, 2687-2701 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cysteine proteinase inhibitor cystatin C inhibited RANKL-stimulated osteoclast formation in mouse bone marrow macrophage cultures, an effect associated with decreased mRNA expression of Acp5, Calcr, Ctsk, Mmp9, Itgb3, and Atp6i, without effect on proliferation or apoptosis. The effects were concentration dependent with half-maximal inhibition at 0.3 μM. Cystatin C also inhibited osteoclast formation when RANKL-stimulated osteoclasts were cultured on bone, leading to decreased formation of resorption pits. RANKL-stimulated cells retained characteristics of phagocytotic macrophages when cotreated with cystatin C. Three other cysteine proteinase inhibitors, cystatin D, Z-RLVG-CHN2 (IC50 0.1 μM), and E-64 (IC50 3 μM), also inhibited osteoclast formation in RANKL-stimulated macrophages. In addition, cystatin C, Z-RLVG-CHN2, and E-64 inhibited osteoclastic differentiation of RANKL-stimulated CD14(+) human monocytes. The effect by cystatin C on differentiation of bone marrow macrophages was exerted at an early stage after RANKL stimulation and was associated with early (4 h) inhibition of c-Fos expression and decreased protein and nuclear translocation of c-Fos. Subsequently, p52, p65, IκBα, and Nfatc1 mRNA were decreased. Cystatin C was internalized in osteoclast progenitors, a process requiring RANKL stimulation. These data show that cystatin C inhibits osteoclast differentiation and formation by interfering intracellularly with signaling pathways downstream RANK.

  • 33.
    Strålberg, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Kassem, Ali
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Kasprzykowski, Franciszek
    Abrahamson, Magnus
    Grubb, Anders
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Inhibition of lipopolysaccharide-induced osteoclast formation and bone resorption in vitro and in vivo by cysteine proteinase inhibitors2017Inngår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 101, nr 5, 1233-1243 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inflammation-induced bone destruction is a major treatment target in many inflammatory skeletal diseases. The aim of this study was to investigate if the cysteine proteinase inhibitors cystatin C, fungal cysteine proteinase inhibitor (E-64), and N-benzyloxycarbonyl-arginylleucyl-valyl-glycyl-diazomethane acetate (Z-RLVG-CHN2) can inhibit LPS-induced osteoclast formation. Mouse bone marrow macrophages (BMMs) were isolated and primed with receptor activator of NF-kappa B ligand (RANKL) for 24 h, followed by stimulation with LPS, with and without inhibitors. Adult mice were injected locally with LPS and then treated with E-64 and osteoclast formation assessed by the number of cathepsin K+ multinucleated cells. Cystatin C inhibited LPS-induced osteoclast formation time and concentration dependently (IC50 = 0.3 mu M). The effect was associated with decreased mRNA and protein expression of tartrate-resistant acid phosphatase (TRAP) and cathepsin K and of the osteoclastogenic transcription factors c-Fos and NFATc1. LPS-induced osteoclast formation on bone slices was also inhibited by cystatin C, resulting in decreased pit formation and release of bone matrix proteins. Similar data were obtained with E-64 and Z-RLVG-CHN2. Cystatin C was internalized in BMMs stimulated by LPS but not in unstimulated BMMs. Osteoclast formation induced by LPS was dependent on TNF-alpha, and the 3 inhibitors abolished LPS-induced TNF superfamily 2 (gene encoding TNF-alpha; Tnfsf2) mRNA expression without affecting Il1b, Il6, or oncostatin M (Osm) expression. Formation of osteoclasts in the skull bones after local LPS stimulation was inhibited by E-64. It is concluded that cysteine proteinase inhibitors effectively inhibit LPS-induced osteoclast formation in vivo and in vitro by inhibition of TNF-alpha expression. The targeting of cysteine proteinases might represent a novel treatment modality for prevention of inflammatory bone loss.

  • 34.
    Windahl, Sara H.
    et al.
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Saxon, Leanne
    Borjesson, Anna E.
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lagerquist, Marie K.
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Frenkel, Baruch
    Henning, Petra
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Molekylär paradontologi.
    Galea, Gabriel L.
    Meakin, Lee B.
    Engdahl, Cecilia
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sjögren, Klara
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Antal, Maria C.
    Krust, Andree
    Chambon, Pierre
    Lanyon, Lance E.
    Price, Joanna S.
    Ohlsson, Claes
    Department of Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Estrogen Receptor-alpha is required for the Osteogenic Response to mechanical loading in a Ligand-Independent manner involving its activation function 1 but Not 22013Inngår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 28, nr 2, 291-301 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Estrogen receptor-alpha (ER alpha) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERa domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERa inactivation (ER alpha(-/-)), (2) specific inactivation of activation function 1 (AF-1) in ER alpha (ER alpha AF-1(0)), or (3) specific inactivation of ER alpha AF-2 (ER alpha AF- 2(0)) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ER alpha(-/-) mice displayed a severely reduced osteogenic response to loading with changes in cortical area (-78% +/- 15%, p < 0.01) and periosteal BFR (-81% +/- 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ER alpha AF-1(0) mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area -40% +/- 11%, p < 0.05 and periosteal BFR -41% +/- 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ER alpha AF-2(0) mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERa is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2. (C) 2013 American Society for Bone and Mineral Research.

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