Abstract
Osteoarthritis (OA) is the most common joint disease characterized by destruction of articular cartilage. OA-induced cartilage degeneration causes inflammation, oxidative stress and the hypertrophic shift of quiescent chondrocytes. Clusterin (CLU) is a ubiquitous glycoprotein implicated in many cellular processes and its upregulation has been recently reported in OA cartilage. However, the specific role of CLU in OA cartilage injury has not been investigated yet. We analyzed CLU expression in human articular cartilage in vivo and in cartilage-derived chondrocytes in vitro. CLU knockdown in OA chondrocytes was also performed and its effect on proliferation, hypertrophic phenotype, apoptosis, inflammation and oxidative stress was investigated. CLU expression was upregulated in human OA cartilage and in cultured OA cartilage-derived chondrocytes compared with control group. CLU knockdown reduced cell proliferation and increased hypertrophic phenotype as well as apoptotic death. CLU-silenced OA chondrocytes showed higher MMP13 and COL10A1 as well as greater TNF-α, Nox4 and ROS levels. Our results indicate a possible cytoprotective role of CLU in OA chondrocytes promoting cell survival by its anti-apoptotic, anti-inflammatory and antioxidant properties and counteracting the hypertrophic phenotypic shift. Further studies are needed to deepen the role of CLU in order to identify a new potential therapeutic target for OA.
Highlights
Osteoarthritis (OA) is the most common joint disease with an increasing prevalence in the elderly population [1]
IL-6 and acetyl-histone H4 (AcH4) are increased in OA cartilage
In order to confirm the “active” inflammatory and transcriptional status of osteoarthritic cartilage [25,26,27], we evaluated by immunohistochemistry the expression of pro-inflammatory cytokine IL-6 and acetyl-histone H4 (AcH4), indicator of transcriptional activity, in articular cartilage of fractured and OA patients
Summary
Osteoarthritis (OA) is the most common joint disease with an increasing prevalence in the elderly population [1]. Chondrocytes of the articular www.aging-us.com cartilage play a central role in maintaining the dynamic equilibrium between anabolism and catabolism of the extracellular matrix under physiological conditions [4]. In OA cartilage, catabolic events prevail in the extracellular matrix [5] and quiescent chondrocytes undergo a phenotypic shift becoming hypertrophic “activated” cells, characterized by a higher proliferation rate with cluster formation and increased production of matrix-degrading enzymes, such as metalloproteinase 13 (MMP13) and aggrecanases [6]. OA-hypertrophic chondrocytes are characterized by increased expression of terminal differentiation markers, including type X collagen (COL10A1), runt-related transcription factor 2 (RUNX2), transglutaminase 2 (TG2) and indian hedgehog (IHH) [7,8,9]. NOX4 isoform, the sole active isoform in human chondrocytes, has been reported to be upregulated in OA [12]
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