CTRP3 exacerbates tendinopathy by dysregulating tendon stem cell differentiation and altering extracellular matrix composition

Abstract

Tendinopathy, the most common disorder affecting tendons, is characterized by chronic disorganization of thetendon matrix, which leads to tendon tear and rupture. The goal was to identify a rational molecular target whoseblockade can serve as a potential therapeutic intervention for tendinopathy. We identified C1q/TNF-relatedprotein-3 (CTRP3) as a markedly up-regulated cytokine in human and rodent tendinopathy. Overexpression ofCTRP3 enhanced the progression of tendinopathy by accumulating cartilaginous proteoglycans and degeneratingcollagenous fibers in the mouse tendon, whereas CTRP3 knockdown suppressed the tendinopathy pathogenesis.Functional blockade of CTRP3 using a neutralizing antibody ameliorated overuse-induced tendinopathy of theAchilles and rotator cuff tendons. Mechanistically, CTRP3 elicited a transcriptomic pattern that stimulates abnormaldifferentiation of tendon stem/progenitor cells and ectopic chondrification as an effect linked to activation of Aktsignaling. Collectively, we reveal an essential role for CTRP3 in tendinopathy and propose a potential therapeuticstrategy for the treatment of tendinopathy.