Chondrocyte mTORC1 activation stimulates miR‐483‐5p via HDAC4 in osteoarthritis progression

The hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) in chondrocytes has been shown to accelerate the severity of destabilization of the medial meniscus‐induced and age‐related osteoarthritis (OA) phenotypes with aberrant chondrocyte hypertrophy and angiogenesis. Meanwhile, we previously reported that miR‐483‐5p is essential for the initiation and development of OA by stimulating chondrocyte hypertrophy and angiogenesis. The connection between mTORC1 and miR‐483‐5p activation in OA progression, however, remains unclear. In this study, we elucidated their relationship and identified the underlying mechanisms. The expression of miR‐483‐5p in the articular cartilage of cartilage‐specific TSC1 knockout mice was assessed compared with control mice using the Agilent Mouse miRNA (8*60K) V19.0 array and real‐time polymerase chain reaction (RT‐PCR). The functional effects of the stimulation of miR‐483‐5p via histone deacetylase 4 (HDAC4) by mTORC1 in OA development, subsequently modulating its downstream targets matrilin 3 and tissue inhibitor of metalloproteinase 2, were examined by immunostaining, western blotting, and real‐time PCR. This study revealed that miR‐483‐5p was responsible for mTORC1 activation‐stimulated OA. Mechanistically, mTORC1 controls the HDAC4‐dependent expression of miR‐483‐5p to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and subchondral bone angiogenesis, and it consequently initiates and accelerates the development of OA. Our findings revealed a novel mTORC1‐HDAC4‐miR‐483‐5p pathway that is critical for OA development.