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.

Expression levels of CXCR4 and CXCL12 in patients with rheumatoid arthritis and its correlation with disease activity

“…CXCL12 can promote the secretion of matrix metalloproteins (MMPs) via chondrocytes, including MMP-1 and by promoting MMP secretion (37). Previous studies have demonstrated that CXCL12 and CXCR4 are closely associated with synovial cell inflammation in patients with RA (17,38), but to the best of our knowledge, no previous reports have discussed the correlation between CXCL12 and CXCR4, or disease activity in patients with RA.…”

“…CXCR4 receptor antagonists have been used to reduce the expression levels of MMP-1 and MMP-13 in synovial fluid in patients with RA ( 36 ). In addition, CXCL12 and CXCR4 can further induce injury of the articular cartilage by promoting MMP secretion ( 37 ). Previous studies have demonstrated that CXCL12 and CXCR4 are closely associated with synovial cell inflammation in patients with RA ( 17 , 38 ), but to the best of our knowledge, no previous reports have discussed the correlation between CXCL12 and CXCR4, or disease activity in patients with RA.…”

Exosomes: roles and therapeutic potential in osteoarthritis

“…The subchondral bone could affect cartilage degeneration through mechanical changes or paracrinemediated bone-cartilage cross-talk. [12][13][14] The cytokines from synovial fibroblasts (SFB) of inflammatory cells could influence the degradation of the cartilage matrix and the formation of osteophytes by releasing proinflammatory factors such as IL-1β and bone-regulated factors including BMP-2. 15 Inflammatory activation of the synovium and infrapatellar fat pad (IPFP) can lead to the release of various proinflammatory mediators that not only cause widespread changes in the structure and function of synovial tissue but also promote articular cartilage damage and accelerate OA development.…”

LncRNA MM2P-induced, exosome-mediated transfer of Sox9 from monocyte-derived cells modulates primary chondrocytes

“…One week after DMM surgery, mice were treated through tail-vein injection. Three weeks later, the mice were killed by cervical dislocation and knee joints were collected for H&E staining or Saffron O staining as previously elucidated 6,33 .…”