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1.
Clin Exp Rheumatol ; 35(3): 406-414, 2017.
Article in English | MEDLINE | ID: mdl-28079506

ABSTRACT

OBJECTIVES: Adiponectin is an effector molecule in the pathophysiology of rheumatoid arthritis, e.g. by inducing cytokines and matrix degrading enzymes in synovial fibroblasts. There is growing evidence that adiponectin affects osteoblasts and osteoclasts although the contribution to the aberrant bone metabolism in rheumatoid arthritis is unclear. Therefore, the adiponectin effects on rheumatoid arthritis-derived osteoblasts and osteoclasts were evaluated. METHODS: Adiponectin and its receptors were examined in bone tissue. Primary human osteoblasts and osteoclasts were stimulated with adiponectin and analysed using realtime polymerase chain-reaction and immunoassays. Effects on matrix-production by osteoblasts and differentiation and resorptive activity of osteoclasts were examined. RESULTS: Immunohistochemistry of rheumatoid arthritis bone tissue showed adiponectin expression in key cells of bone remodelling. Adiponectin altered gene expression and cytokine release in osteoblasts and increased IL-8 secretion by osteoclasts. Adiponectin inhibited osterix and induced osteoprotegerin mRNA in osteoblasts. In osteoclasts, MMP-9 and tartrate resistant acid phosphatase expression was increased. Accordingly, mineralisation capacity of osteoblasts decreased whereas resorptive activity of osteoclasts increased. CONCLUSIONS: The results confirm the proinflammatory potential of adiponectin and support the idea that adiponectin influences rheumatoid arthritis bone remodelling through alterations in osteoblast and osteoclast.


Subject(s)
Adiponectin/pharmacology , Arthritis, Rheumatoid/pathology , Bone Remodeling/drug effects , Osteoblasts/drug effects , Osteoclasts/drug effects , Adult , Aged , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Bone Resorption/metabolism , Bone Resorption/pathology , Calcification, Physiologic/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Female , Gene Expression Regulation , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Middle Aged , Osteoblasts/metabolism , Osteoblasts/pathology , Osteoclasts/metabolism , Osteoclasts/pathology , Osteogenesis/drug effects , Osteoprotegerin/genetics , Osteoprotegerin/metabolism , Receptors, Adiponectin/agonists , Receptors, Adiponectin/genetics , Receptors, Adiponectin/metabolism , Sp7 Transcription Factor , Tartrate-Resistant Acid Phosphatase/genetics , Tartrate-Resistant Acid Phosphatase/metabolism , Time Factors , Transcription Factors/genetics , Transcription Factors/metabolism
2.
Matrix Biol ; 62: 75-91, 2017 10.
Article in English | MEDLINE | ID: mdl-27884778

ABSTRACT

OBJECTIVE: Osteophyte formation in osteoarthritis (OA) is mediated by increased osteoblast activity, which is -in turn- regulated by the Wnt signaling pathway. Obesity is regarded a risk factor in OA, yet little is known about the interaction between adipose tissue-derived factors, the adipokines, and bone formation, although adipokines are associated with the pathogenesis of OA. Therefore, the effect of adipokines on bone and cartilage forming cells and osteophyte development was analyzed. METHODS: Human OA osteophytes were histologically characterized and adipokine expression was evaluated by immunohistochemistry. Osteoblasts and chondrocytes were isolated from OA tissue and stimulated with adiponectin, resistin, or visfatin. Cytokine and osteoblast/chondrocyte markers were quantified and activation of Wnt and p38 MAPK signaling was analyzed. RESULTS: Adiponectin, resistin, and visfatin were expressed in OA osteophytes by various articular cell types. Stimulation of OA osteoblasts with adiponectin and of OA chondrocytes with visfatin led to an increased release of proinflammatory mediators but not to osteoblast differentiation or activation. Additionally, visfatin increased matrix degrading factors in chondrocytes. Wnt signaling was not altered by adipokines, but adiponectin induced p38 MAPK signaling in osteoblasts. CONCLUSION: Adipokines are present in OA osteophytes, and adiponectin and visfatin increase the release of proinflammatory mediators by osteoblasts and chondrocytes. The effects of adiponectin were mediated by p38 MAPK but not Wnt signaling in osteoblasts. Therefore, the results support the idea that adipokines do not directly influence osteophyte development but the proinflammatory conditions in OA.


Subject(s)
Adiponectin/metabolism , Cytokines/metabolism , Nicotinamide Phosphoribosyltransferase/metabolism , Osteoarthritis/complications , Osteoblasts/cytology , Osteophyte/metabolism , Resistin/metabolism , Aged , Aged, 80 and over , Cell Differentiation , Cells, Cultured , Chondrocytes/cytology , Chondrocytes/metabolism , Female , Gene Expression Regulation , Humans , MAP Kinase Signaling System , Male , Osteoarthritis/metabolism , Osteoblasts/metabolism , Wnt Signaling Pathway
3.
Joint Bone Spine ; 83(1): 63-7, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26076655

ABSTRACT

OBJECTIVE: Osteoarthritis is not only characterized by cartilage degradation but also involves subchondral bone remodeling and osteophyte formation. Osteophytes are fibrocartilage-capped bony outgrowths originating from the periosteum. The pathophysiology of osteophyte formation is not completely understood. Yet, different research approaches are under way. Therefore, a histological osteophyte classification to achieve comparable results in osteophyte research was established for application to basic science research questions. METHODS: The osteophytes were collected from knee joints of osteoarthritis patients (n=10, 94 osteophytes in total) after joint replacement surgery. Their size and origin in the respective joint were photo-documented. To develop an osteophyte classification, serial tissue sections were evaluated using histological (hematoxylin and eosin, Masson's trichrome, toluidine blue) and immunohistochemical staining (collagen type II). RESULTS: Based on the histological and immunohistochemical evaluation, osteophytes were categorized into four different types depending on the degree of ossification and the percentage of mesenchymal connective tissue. Size and localization of osteophytes were independent from the histological stages. CONCLUSION: This histological classification system of osteoarthritis osteophytes provides a helpful tool for analyzing and monitoring osteophyte development and for characterizing osteophyte types within a single human joint and may therefore contribute to achieve comparable results when analyzing histological findings in osteophytes.


Subject(s)
Knee Joint/pathology , Osteoarthritis, Knee/pathology , Osteophyte/pathology , Aged , Arthroplasty, Replacement, Knee , Female , Humans , Immunohistochemistry , Male , Middle Aged , Osteoarthritis, Knee/surgery
4.
J Clin Invest ; 122(5): 1791-802, 2012 May.
Article in English | MEDLINE | ID: mdl-22505457

ABSTRACT

Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.


Subject(s)
Autoantibodies/metabolism , Bone Resorption/immunology , Citrulline/immunology , Osteoclasts/physiology , Vimentin/immunology , Animals , Antibody Specificity , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Autoantibodies/isolation & purification , Biomarkers/blood , Bone and Bones/immunology , Bone and Bones/pathology , Case-Control Studies , Cell Differentiation , Cells, Cultured , Collagen Type I/blood , Humans , Hydrolases/metabolism , Mice , Mice, Transgenic , Osteoclasts/enzymology , Osteoclasts/metabolism , Protein Processing, Post-Translational , Protein-Arginine Deiminase Type 4 , Protein-Arginine Deiminases , Tumor Necrosis Factor-alpha/blood
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