OA causes severe pain-dysfunction as extracellular matrix (ECM) of articular cartilage gradually degrades with advanced age. The EU-funded 'SIRT1 regulation of aggrecan expression in human chondrocytes' (EUCUREOA) project investigated the molecular mechanism by which the SIRT1 enzyme regulates cartilage-specific gene expression of aggrecan (ACAN) and collagen 2A1 (COL2A1). Aggrecan is a critical component for maintaining cartilage structure and joint resilience, while COL2A1 fibers bestow the joint with the capacity to withstand tensile forces. Since SIRT1 is augmented in healthy cartilage cells (i.e. chondrocytes) and correlates with high expression levels of ACAN and COL2A1, the researchers investigated whether SIRT1 directly induces the expression of both anabolic genes. The results point out that active SIRT1 is required for the expression of ACAN and COL2A1. Moreover, given that inflammation contributes to cartilage destruction during OA, the team investigated whether inflammation could impact SIRT1 activity. Results showed that in the presence of inflammatory cytokines, SIRT1 was cleaved by cathepsin B in chondrocytes. SIRT1 cleavage reduced its enzymatic activity and capacity to activate its gene targets, as COL2A1. Paradoxically, the cleaved fragment of SIRT1 enabled the cells to survive an inflammatory environment, at the expense of their anabolic functions. Further research into the exact role of SIRT1 and its impact on cartilage formation and maintenance will be applicable in drug development to combat OA through control of the SIRT1s activity.
Cartilage, osteoarthritis, inflammation, Sirt1, extracellular matrix