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

Chuangxin Lin,Zhong-Kai Cui,Yuhui Chen,Hong Wang,Haiyan Zhang,Hang Fang,Rongkai Zhang,Liangliang Liu,Chang Zhao,Chun Zeng,Yan Shao,Xiaochun Bai,Daozhang Cai,Pinling Lai

doi:10.1038/s41413-018-0041-8

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.

Highlights

Osteoarthritis (OA) is a highly prevalent and degenerative joint disorder which mainly affects the weight-bearing joints such as hips and knees, and is the leading cause of physical disability,[1,2,3] presenting an enormous clinical and financial burden
We have previously shown that mechanistic target of rapamycin complex 1 (mTORC1) coordi- occurred at the late stages of OA (Fig. 1a), as manifested by an nates chondrocyte growth, proliferation, and differentiation, and increase in osteoclast number as well as larger subchondral bone that mTORC1 activation in turn activates articular cartilage marrow cavities at 2 weeks, and subsequently a decrease in the chondrocytes and initiates OA, while its deletion or inhibition in osteoclast number to baseline at 6 weeks after surgery (Fig. 1d, e). chondrocyte prevents OA development.[22,23]
MTORC1 activation could be detected in some mature osteoblasts (OCN+) during OA development in ACL transection (ACLT) mice (Supplementary Fig. 2b–c)

Summary

Introduction

Osteoarthritis (OA) is a highly prevalent and degenerative joint disorder which mainly affects the weight-bearing joints such as hips and knees, and is the leading cause of physical disability,[1,2,3] presenting an enormous clinical and financial burden. Activation of mTORC1 was detected in tibial subchondral and secretion of Cxcl[12] to promote cartilage degeneration; bone tissues isolated from ACLT mice[33] at 2, 6, and 12 weeks post pharmaceutical inhibition of the pathway might be a promising surgery (Fig. 2a).

Results

Conclusion