REST corepressor (CoREST) repression induces phenotypic gene regulation in advanced osteoarthritic chondrocytes

Abstract

Alternations in cartilage chondrocyte phenotype characteristic by the decreased type II collagen and aggrecan together with increased type X collagen synthesis serve as a beacon for osteoarthritis progression. However, little is known about the underlying molecular mechanisms. The current study seeks to discover molecules that involved in osteoarthritic chondrocytes phenotype regulation. Differential proteomics was generated with two-dimensional gel electrophoresis between normal articular cartilage (NAC) and advanced osteoarthritic cartilage (AOC). Those differentially expressed proteins were identified by mass spectrometry. The down-regulation of a neuronal silencer, the REST corepressor (CoREST) in AOC, was verified by Western blot. CoREST silencing was performed in primarily cultured NAC chondrocytes with specific siRNA to reveal the possible involvement of CoREST repression in chondrocyte phenotypic genes modulation. Ninteen differentially expressed proteins were screened and identified. Among these proteins, CoREST, HHL, and zinc finger protein 155 were estimated to be possible gene modulators. CoREST protein level was verified to be down-regulated by 69.5% (p < 0.001) in AOC. In response to CoREST knock-down by 64.8% (p < 0.001) in NAC chondrocytes, the gene expression level of the chondrocyte terminal differentiation marker gene, collagen X was found to be up-regulated by 40.0% (p = 0.017), whereas the chondrocyte differentiation phenotypic genes, collagen II and aggrecan were down-regulated by 71.4% (p < 0.001) and 57.6% (p < 0.001), respectively. The results indicate that the silencing of CoREST by siRNA transfection in NAC may reflect CoREST repression in AOC, which results in phenotypic genes modulation and suggests a homeostatic role of this transcription factor in articular chondrocyte. © Osteoarthritis (OA) is a disease characteristic of progressive cartilage degeneration and abrasion. The central pathogenesis underlying cartilage degeneration is the imbalance between cartilage matrix proteins synthesis and catabolism, 1 whereby the pathobiology of osteoarthritic chondrocytes is of a central concern. Aside from the increased degradative enzyme activity, the phenotype alternations of chondrocytes in advanced OA cartilage lead to hypoactive anabolism, which serves as an important mechanism for OA progression. 1The normal articular chondrocytes are characteristic of phenotypic type II collagen and aggrecan expression. In the early process of OA, articular chondrocytes increase type II collagen and aggrecan synthesis in an attempt to repair cartilage lesions.2 However, as OA progresses to an advanced stage, chondrocytes begin to express heterogenous phenotypes representatively, type X collagen, 3−6 in conjunction with decreases in type II collagen and aggrecan expression, which reduces the capability of the OA cartilage to repair lesions naturally. 7,8 Chondrocyte phenotype alternations serve as an important cellular event in OA progression, however,

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