SOX9 is a regulator of ADAMTSs-induced cartilage degeneration at the early stage of human osteoarthritis

Abstract

Objective: To identify whether cartilage master regulator SRY-related protein 9 (SOX9) mediates A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) dysregulation during osteoarthritis (OA) cartilage degeneration.

Method: Twenty-two randomly selected OA patients were evaluated using Outerbridge Classification via arthroscopy. Haematoxylin-eosin (HE), Safranin O and Masson staining were performed for the histopathological assessment. The expression of ADAMTSs, collagen 2A1 (COL2A1), aggrecan (ACAN), cartilage oligomeric matrix protein (COMP) and SOX9 were examined using real-time quantitative Polymerase Chain Reaction (PCR) (RT-qPCR) and western blotting analysis. Immunohistochemistry (IHC) analysis was performed to investigate the production of ADAMTSs in cartilage tissues. The association between SOX9 production and ADAMTSs, COL2A1, ACAN, and COMP expression was established by full-depth cartilage biopsies.

Results: ADAMTSs expression levels were repressed at stage 1, while a significant increase was observed at the progressive stage of OA. SOX9 was upregulated at stage 1 and suppressed at a later stage of cartilage development, particularly in cartilage with severe damage. In addition, SOX9 repressed the expression of ADAMTSs and promoted COL2A1, ACAN and COMP expression in human chondrocytes. SOX9 was recruited to the promoters of ADAMTS-4 and ADAMTS-7. SOX9 expression was negatively correlated with ADAMTSs production and was positively associated with COL2A1, ACAN and COMP expression. Inhibition of ADAMTSs markedly increased the production of COL2A1, ACAN and COMP in chondrocytes isolated from the early stage of OA.

Conclusions: These findings indicated that SOX9 upregulation might mediate ADAMTSs suppression at the early stage of human OA. In addition, SOX9 could be used as a potential therapeutic agent for human OA at an early stage.

Keywords: ADAMTS; Cartilage; Chondrocyte; Osteoarthritis; SOX9.