Overexpression of mechanical sensitive miR-337-3p alleviates ectopic ossification in rat tendinopathy model via targeting IRS1 and Nox4 of tendon-derived stem cells

摘要

Tendinopathy,which is characterized by the ectopic ossification of tendon,is a common disease occurring in certain population,such as athletes that suffer from repetitive tendon strains.However,the molecular mechanism underlying the pathogenesis of tendinopathy caused by the overuse of tendon is still lacking.Here,we found that the mechanosensitive miRNA,miR-337-3p,had lower expression under uniaxial cyclical mechanical loading in tendon-derived stem cells(TDSCs)and negatively controlled chondro-osteogenic differentiation of TDSCs.Importantly,downregulation of miR-337-3p expression was also observed in both rat and human calcified tendons,and overexpressing miR-337-3p in patellar tendons of rat tendinopathy model displayed a robust therapeutic efficiency.Mechanistically,we found that the proinflammatory cytokine interleukin-1^was the upstream factor of miR-337-3p that bridges the mechanical loading with its downregulation.Furthermore,the target genes of miR-337-3p,NADPH oxidase 4,and insulin receptor substrate 1,activated chondro-osteogenic differentiation of TDSCs through JNK and ERK signaling,respectively.Thus,these findings not only provide novel insight into the molecular mechanisms underlying ectopic ossification in tendinopathy but also highlight the significance of miR-337-3p as a putative therapeutic target for clinic treatment of tendinopathy.