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

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. Arthritis: Activation of mTORC1 promotes osteoarthritis by stimulating bone sclerosis Mammalian target of rapamycin complex 1 (mTORC1) is a protein complex that controls protein synthesis, and activation of mTORC1 in subchondral preosteoblasts promotes arthritis by stimulating bone sclerosis (abnormal hardening) and secreting C-X-C motif chemokine 12 (CXCL12). Subchondral preosteoblasts are cells that differentiate into bone-forming cells below the cartilage in joints, and CXCL12 is a protein that regulates a wide range of cellular activities. A team headed by Daozhang Cai and Xiaochun Bai of The Third Affiliated Hospital of Southern Medical University, Guangzhou, China investigated mTORC1 activity in subchondral preosteoblasts from osteoarthritis patients and mice. The team found that mTORC1 activation of subchondral preosteoblasts promoted osteoarthritis by stimula