Protection from osteoarthritis: targeting mTOR and autophagy

BACKGROUND and OBJECTIVES: mTOR (a serine/threonine protein kinase) is a major repressor of autophagy, a cell survival mechanism. The specific in vivo mechanism of mTOR signalling in OA pathophysiology is not fully characterised. We determined the expression of mTOR and known autophagy genes in human OA cartilage as well as mouse and dog models of experimental OA. We created cartilage-specific mTOR knockout (KO) mice to determine the specific role of mTOR in OA pathophysiology and autophagy signalling in vivo. METHODS: Inducible cartilage-specific mTOR KO mice were generated and subjected to mouse model of OA. Human OA chondrocytes were treated with rapamycin and transfected with Unc51–like kinase 1 (ULK1) siRNA to determine mTOR signalling. RESULTS: mTOR is overexpressed in human OA cartilage as well as mouse and dog experimental OA. This correlates with increased chondrocyte apoptosis and reduced expression of key autophagy genes during OA. Subsequently, we show for the first time that cartilagespecific ablation of mTOR results in increased autophagy signalling and a significant protection from destabilization of medial meniscus (DMM)-induced OA associated with a significant reduction in the articular cartilage degradation, apoptosis and synovial fibrosis. Further, we show that regulation of ULK1/adenosine monophosphate-activated protein kinase (AMPK) signalling pathway by mTOR may partially be responsible for regulating autophagy signalling and the balance between catabolic and anabolic factors in the articular cartilage. CONCLUSIONS: This study provides a direct evidence of the role of mTOR and its downstream modulation of autophagy in articular cartilage homeostasis. Thus targeting cellular homeostasis mediators, such as mTOR and its downstream signaling by autophagy pathway may be a promising therapeutic strategy to achieve chondroprotection and correct the imbalance between catabolic and anabolic processes during OA and related disorders.