mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis

Abstract

Objective: 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.

Method: 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^ER) mice were generated. The functional effects of mTORC1 in OA initiation and development on its downstream targets were examined by immunostaining, western blotting and qPCR.

Results: Articular chondrocyte mTORC1 was activated in early-stage OA and in aged mice. TSC1CKO mice exhibited spontaneous OA, and TSC1CKO^ER mice (from 2 months) exhibited accelerated age-related and DMM-induced OA phenotypes, with aberrant chondrocyte proliferation and hypertrophic differentiation. This was associated with hyperactivation of mTORC1 and dramatic downregulation of FGFR3 and PPR, two receptors critical for preventing chondrocyte proliferation and differentiation. Rapamycin treatment reversed these phenotypes in KO mice. Furthermore, in vitro rescue experiments demonstrated that p73 and ERK1/2 may mediate the negative regulation of FGFR3 and PPR by mTORC1.

Conclusion: mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.

Keywords: Chondrocyte; FGFR3; Osteoarthritis; PPR; mTORC1.