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 posttraumatic 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.

FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis(RA).Fatty acid-binding protein 4(FABP4),a novel adipokine that regulates inflammation and angiogenesis,has been extensively studied in a variety of organs and diseases.However,the effect of FABP4 on RA remains unclear.Here,we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA.The increase in FABP4 promoted synovitis,angiogenesis,and cartilage degradation to exacerbate RA progression in vivo and in vitro,whereas BMS309403(a FABP4 inhibitor)and anagliptin(dipeptidyl peptidase 4 inhibitor)inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression.Further studies showed that constitutive activation of mammalian target of rapamycin complex 1(mTORC1)by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice.In contrast,inhibition of mTORC1 by ras homolog enriched in brain(Rheb1)disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice.Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis,angiogenesis,and cartilage degradation in RA.BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development.Hence,FABP4 may represent a potential target for RA therapy.