Abstract
Tendinopathy poses a formidable challenge due to the inherent limitations of tendon regenerative capabilities post-injury. At present, effective curative approaches for tendinopathy are still lacking. Collagen triple helix repeat-containing 1 (CTHRC1) is an extracellular matrix protein with significant roles in both physiological and pathological processes. The present study aims to investigate the function and underlying mechanism of CTHRC1 in tendinopathy. In this study, CTHRC1 is identified as a potential effector in promoting tendon regeneration through multi-proteomic analysis of Achilles tendon tissues in mice. In vitro, CTHRC1 enhances the proliferation, migration, and tenogenic differentiation of tendon stem/progenitor cell (TSPC). In vivo, CTHRC1 deletion impairs tendon healing, while its overexpression reverses the detrimental effects caused by CTHRC1 deficiency. Mechanistically, proteomics on TSPC stimulated with recombinant CTHRC1 reveal that CTHRC1 activates the mitogen-activated protein kinase (MAPK) signaling pathway via binding to epidermal growth factor receptor (EGFR), which in turn promotes the proliferative, migrative, and tenogenic capacities of TSPC to attenuate Achilles tendinopathy. Conversely, inhibiting EGFR reverses the tendon-healing effect of CRHRC1. The study demonstrates that CTHRC1 can promote the proliferative, migrative, and tenogenic capacities of TSPC, ultimately facilitating tendon healing through activating the EGFR/MAPK signaling pathway. CTHRC1 holds promise as a potential intervention for tendinopathy.