Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis

Contains fulltext : 153537.pdf (publisher's version ) (Closed access)OA is a degenerative joint disease characterized by articular cartilage degradation, osteophyte formation, synovitis, and subchondral bone sclerosis. One of OAs main risk factors is obesity. To date, it is not fully understood how obesity results in OA. Historically, this link was ascribed to excessive joint loading as a result of increased body weight. However, the association between obesity and OA in non-weight-bearing joints suggests a more complex aetiology for obesity-induced OA. In the present review, the link between obesity and OA is discussed. First, the historical view of altered joint loading leading to wear and tear of the joint is addressed. Subsequently, the effects of a disturbed lipid metabolism, low-grade inflammation, and adipokines on joint tissues are discussed and linked to OA. Taken together, inflamed adipose tissue and dyslipidaemia play pivotal roles in obesity-induced OA. It becomes increasingly clear that the link between obesity and OA transcends excessive loading

TGF-beta dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression

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The high affinity ALK1-ligand BMP9 induces a hypertrophy-like state in chondrocytes that is antagonized by TGFbeta1

Item does not contain fulltextOBJECTIVE: In osteoarthritic cartilage, expression of the receptor ALK1 correlates with markers of deleterious chondrocyte hypertrophy. Recently, bone morphogenetic protein 9 (BMP9) was identified as a high affinity ligand for ALK1. Therefore, we studied if BMP9 signaling results in expression of hypertrophy markers in chondrocytes. Furthermore, because transforming growth factorss1 (TGFbeta1) is a well known anti-hypertrophic factor, the interaction between BMP9 and TGFbeta1 signaling was also studied. DESIGN: Primary chondrocytes were isolated from bovine cartilage and stimulated with BMP9 and/or TGFbeta1 to measure intracellular signaling via pSmads with the use of Western blot. Expression of Smad-responsive genes or hypertrophy-marker genes was measured using qPCR. To confirm observations on TGFbeta/Smad3 responsive genes, a Smad3-dependent CAGA12-luc transcriptional reporter assay was performed in the chondrocyte G6 cell line. RESULTS: In primary chondrocytes, BMP9 potently induced phosphorylation of Smad1/5 and Smad2 to a lesser extent. BMP9-induced Smad1/5 phosphorylation was rapidly (2 h) reflected in gene expression, whereas Smad2 phosphorylation was not. Remarkably, BMP9 and TGFbeta1 dose-dependently synergized on Smad2 phosphorylation, and showed an additive effect on expression of Smad3-dependent genes like bSerpine1 after 24 h. The activation of the TGFbeta/Smad3 signaling cascade was confirmed using the CAGA12-luc transcriptional reporter. BMP9 selectively induced bAlpl and bColX expression, which are considered early markers of cellular hypertrophy, but this was potently antagonized by addition of a low dose of TGFbeta1. CONCLUSIONS: This study shows that in vitro in chondrocytes, BMP9 potently induces pSmad1/5 and a chondrocyte hypertrophy-like state, which is potently blocked by TGFbeta1. This observation underlines the importance of TGFbeta1 in maintenance of chondrocyte phenotype

Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage

Contains fulltext : 153159.pdf (publisher's version ) (Closed access)OBJECTIVES: In osteoarthritis (OA) chondrocytes surrounding lesions express elevated bone morphogenetic protein 2 (BMP2) levels. To investigate the functional consequence of chondrocyte-specific BMP2 expression, we made a collagen type II dependent, doxycycline (dox)-inducible BMP2 transgenic mouse and studied the effect of elevated BMP2 expression on healthy joints and joints with experimental OA. METHODS: We cloned a lentivirus with BMP2 controlled by a tet-responsive element and transfected embryos of mice containing a collagen type II driven cre-recombinase and floxed rtTA to gain a mouse expressing BMP2 solely in chondrocytes and only upon dox exposure (Col2-rtTA-TRE-BMP2). Mice were treated with dox to induce elevated BMP2 expression. In addition, experimental OA was induced (destabilisation of the medial meniscus model) with or without dox supplementation and knee joints were isolated for histology. RESULTS: Dox treatment resulted in chondrocyte-specific upregulation of BMP2 and severely aggravated formation of osteophytes in experimental OA but not in control mice. Moreover, elevated BMP2 levels did not result in alterations in articular cartilage of young healthy mice, although BMP2-exposure did increase VDIPEN expression in the articular cartilage. Strikingly, despite apparent changes in knee joint morphology due to formation of large osteophytes there were no detectible differences in articular cartilage: none with regard to structural damage nor in Safranin O staining intensity when comparing destabilisation of the medial meniscus with or without dox exposure. CONCLUSIONS: Our data show that chondrocyte-specific elevation of BMP2 levels does not alter the course of cartilage damage in an OA model in young mice but results in severe aggravation of osteophyte formation

TGF beta-mediated expression of TGF beta-activating integrins in SSc monocytes: disturbed activation of latent TGF beta?

Contains fulltext : 217417.pdf (publisher's version ) (Open Access