RICTOR-mediated activation of AKT/mTOR signaling and autophagy inhibition promote osteoarthritis.

The most common joint disease in the elderly is osteoarthritis (OA), which is characterized by synovitis, cartilage degeneration, and osteophytes, for which there are currently no effective therapies. Chondrocytes, responsible for extracellular matrix (ECM) synthesis and degradation, undergo changes in OA, leading to ECM disruption and disease progression. There is no clear role for the Mechanistic target of rapamycin complex 2 (mTORC2) in OA, but it is known to regulate cellular functions, such as proliferation, metabolism, motility, and apoptosis. The purpose of this study was to determine the molecular mechanism by which Rapamycin-insensitive companion of mTOR (RICTOR), a component of mTORC2, contributes to OA progression. The results demonstrate that IL-1β induces high expression of RICTOR in chondrocytes, promoting downregulation of collagen II expression and impairing autophagy. Silencing RICTOR reverses IL-1β-induced downregulating of collagen II expression and mitochondrial dysfunction. RICTOR inhibits chondrocyte autophagy by inhibiting autophagosome formation and preventing autophagosome-lysosome fusion. Additionally, RICTOR promotes oxidative stress in chondrocytes, leading to disruption of normal mitochondrial structure and disturbance of the articular cartilage microenvironment. This study reveals the potential of RICTOR to treat OA. Specifically, blocking mTORC2 might be an effective treatment strategy.