Articular chondrocyte activation, involving aberrant proliferation and prehypertrophic differentiation, is essential for osteoarthritis (OA) initiation and progression. Disruption of mechanistic target of rapamycin complex 1 (mTORC1) promotes chondrocyte autophagy and survival, and decreases the severity of experimental OA. However, the role of cartilage mTORC1 activation in OA initiation is unknown. In this study, we elucidated the specific role of mTORC1 activation in OA initiation, and identify the underlying mechanisms.
Expression of mTORC1 in articular cartilage of OA patients and OA mice was assessed by immunostaining. Cartilage-specific tuberous sclerosis complex 1 (Tsc1, mTORC1 upstream inhibitor) knockout (TSC1CKO) and inducible Tsc1 KO (TSC1CKO
Articular chondrocyte mTORC1 was activated in early-stage OA and in aged mice. TSC1CKO mice exhibited spontaneous OA, and TSC1CKO
mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.