Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12

Abstract

Increasing evidences show that aberrant subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). However, how subchondral bone formation is activated and the mechanism by which increased subchondral bone turnover promotes cartilage degeneration during OA remains unclear. Here, we show that the mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in subchondral bone preosteoblasts (Osterix+) from OA patients and mice. Constitutive activation of mTORC1 in preosteoblasts by deletion of the mTORC1 upstream inhibitor, tuberous sclerosis 1, induced aberrant subchondral bone formation, and sclerosis with little-to-no effects on articular cartilage integrity, but accelerated post-traumatic OA development in mice. In contrast, inhibition of mTORC1 in preosteoblasts by disruption of Raptor (mTORC1-specific component) reduced subchondral bone formation and cartilage degeneration, and attenuated post-traumatic OA in mice. Mechanistically, mTORC1 activation promoted preosteoblast expansion and Cxcl12 secretion, which induced subchondral bone remodeling and cartilage degeneration during OA. A Cxcl12-neutralizing antibody reduced cartilage degeneration and alleviated OA in mice. Altogether, these findings demonstrate that mTORC1 activation in subchondral preosteoblasts is not sufficient to induce OA, but can induce aberrant subchondral bone formation and secrete of Cxcl12 to accelerate disease progression following surgical destabilization of the joint. Pharmaceutical inhibition of the pathway presents a promising therapeutic approach for OA treatment.

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Funding

National Natural Science Foundation of China(Grant No 81625015,81530070)and the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37).

National Natural Science Foundation of China(Grant No 81601945).

National Natural Science Foundation of China(Grant No 81371990).

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