Abstract
Obesity is a risk factor for osteoarthritis (OA) development and progression due to an altered biomechanical stress on cartilage and an increased release of inflammatory adipokines from adipose tissue. Evidence suggests an interplay between loading and adipokines in chondrocytes metabolism modulation. We investigated the role of loading, as hydrostatic pressure (HP), in regulating visfatin-induced effects in human OA chondrocytes. Chondrocytes were stimulated with visfatin (24 h) and exposed to high continuous HP (24 MPa, 3 h) in the presence of visfatin inhibitor (FK866, 4 h pre-incubation). Apoptosis and oxidative stress were detected by cytometry, B-cell lymphoma (BCL)2, metalloproteinases (MMPs), type II collagen (Col2a1), antioxidant enzymes, miRNA, cyclin D1 expressions by real-time PCR, and β-catenin protein by western blot. HP exposure or visfatin stimulus significantly induced apoptosis, superoxide anion production, and MMP-3, -13, antioxidant enzymes, and miRNA gene expression, while reducing Col2a1 and BCL2 mRNA. Both stimuli significantly reduced β-catenin protein and increased cyclin D1 gene expression. HP exposure exacerbated visfatin-induced effects, which were counteracted by FK866 pre-treatment. Our data underline the complex interplay between loading and visfatin in controlling chondrocytes’ metabolism, contributing to explaining the role of obesity in OA etiopathogenesis, and confirming the importance of controlling body weight for disease treatment.
Highlights
Obesity represents one of the most influential risk factors for osteoarthritis (OA) incidence, progression, and disability [1]
The exposure of the cells to hydrostatic pressure (HP) significantly reduced the percentage of survival and the transcriptional levels of the anti-apoptotic marker BCL2, while it raised apoptosis and induced an up-regulation of MMP-3, MMP-13 gene expression, and a decrease of Col2a1, in comparison to the basal condition (p < 0.01, Figure 1A–F)
Our results showed the up-regulation of the gene expression of matrix-degrading enzymes, MMP-3 and MMP-13, and the reduction of Col2a1 in OA chondrocytes exposed to HP or stimulated with visfatin, in agreement with previous studies [6,8,9,13,27,29,39,40,41,42,43]
Summary
Obesity represents one of the most influential risk factors for osteoarthritis (OA) incidence, progression, and disability [1]. Several in vitro studies demonstrated that the application of injurious static HP induced chondrocyte catabolic processes, including degradation of extracellular matrix (ECM) components, production of inflammatory cytokines, oxidative stress, and dysregulation of miRNA expression [6,7,8,9,10,11,12,13,14]. Adipokines, including adiponectin, leptin, resistin, chemerin, and visfatin, are metabolically active proteins that emerged as crucial regulators of immune system response and chronic inflammation [18,19]. Their critical role in the pathogenesis of immune-mediated rheumatic diseases and degenerative OA has been amply demonstrated [20,21,22,23]. Circulating visfatin levels were found higher in patients with OA than those in healthy controls [20,26]; pro-inflammatory, catabolic, and pro-degradative effects of visfatin in OA chondrocytes and synovial fibroblasts were revealed [27,28,29,30]
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