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

ABSTRACT: Tendinopathy, the most common disorder affecting tendons, is characterized by chronic disorganization of the tendon matrix, which eventually leads to tendon tear and rupture. The goal of this study was to identify a rational molecular target whose blockade can serve as a potential therapeutic intervention for tendinopathy. We identified C1q/TNF-related protein-3 (CTRP3) as a markedly upregulated cytokine in human and rodent tendinopathy. Overexpression of CTRP3 enhanced the progression of tendinopathy by accumulating cartilaginous proteoglycans and degenerating collagenous 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 the Achilles and rotator cuff tendons. Mechanistically, CTRP3 elicited a transcriptomic pattern that stimulates abnormal differentiation of tendon stem/progenitor cells (TSPCs) and ectopic chondrification in tendons, as an effect linked to activation of Akt signaling. Collectively, we reveal an essential role for CTRP3 in tendinopathy and propose a potential therapeutic strategy for the treatment of tendinopathy.

ORGANISM(S): Mus musculus

PROVIDER: GSE180368 | GEO | 2021/10/02

REPOSITORIES: GEO

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

Project description:Tendinopathy, the most common disorder affecting tendons, is characterized by chronic disorganization of the tendon matrix, which eventually leads to tendon tear and rupture. The goal of this study was to identify a rational molecular target whose blockade can serve as a potential therapeutic intervention for tendinopathy. We identified C1q/TNF-related protein-3 (CTRP3) as a markedly upregulated cytokine in human and rodent tendinopathy. Overexpression of CTRP3 enhanced the progression of tendinopathy by accumulating cartilaginous proteoglycans and degenerating collagenous 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 the Achilles and rotator cuff tendons. Mechanistically, CTRP3 elicited a transcriptomic pattern that stimulates abnormal differentiation of tendon stem/progenitor cells (TSPCs) and ectopic chondrification in tendons, as an effect linked to activation of Akt signaling. Collectively, we reveal an essential role for CTRP3 in tendinopathy and propose a potential therapeutic strategy for the treatment of tendinopathy.

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Project description:Adult tendon stem/progenitor cells (TSPCs) are essential for tendon maintenance, regeneration, and repair, yet they become susceptible to senescence with age, impairing the self-healing capacity of tendons. In this study, we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness. The top-ranked candidate prim-O-glucosylcimifugin (POG), a saposhnikovia root extract, could ameliorate TPSC- senescent phenotypes caused by long-term passage and natural aging in rats and humans, as well as restore self-renewal and proliferation capacities, and tenogenic potential of aged TSPCs. In vivo, the systematic administration of POG or the local delivery of POG nanoparticles functionally rescues endogenous tendon regeneration and repair capacity in aged rats to levels similar to normal animals. Mechanistically, POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and downregulating mTOR signaling with induction of autophagy. Together, the strategy by pharmacological intervention with deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons. We performed mRNA microarray analyses of DMSO-treated and POG-treated TSPCs from 18-month-old rats and identified meaningful genes in down-regulated and up-regulated group

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