S100A11 Regulates Tenocyte-Derived Stem Cell Apoptosis via the UCHL3/Bcl- 2/Bax/Caspase3 Signalling Pathway and Influences Tendinopathy Healing

Background Tendinopathy impairs quality of life because of inherently slow and incomplete tendon healing, which is often linked to excessive apoptosis of tendon-derived stem cells (TDSCs) through disruption of the Bcl-2/BAX/caspase-3 balance. Methods This study identified S100A11 via proteomic profiling of clinical tendon tissues. We investigated the role of S100A11 using TNF-α-induced TDSC apoptosis models, S100A11 knockdown or overexpression, apoptosis pathway analysis, UCHL3 coimmunoprecipitation, and a mouse rotator cuff tear model to compare wild-type (WT) and S100A11−/− mice. Results S100A11 expression was elevated in tendinopathic tissue and apoptotic TDSCs. S100A11 knockdown suppressed TDSC apoptosis by increasing the expression of Bcl-2 and decreasing that of Bax and cleaved caspase3. S100A11 overexpression promoted apoptosis, which was reversed by the BAX inhibitor BAI1. S100A11 physically interacted with UCHL3, and UCHL3 addition reversed S100A11-induced apoptosis. Crucially, compared with WT mice, S100A11−/− mice exhibited reduced tendon apoptosis, accelerated tendon remodelling, and superior biomechanical properties after injury. Conclusion S100A11 promotes TDSC apoptosis via the Bcl-2/BAX/caspase-3 pathway, which is potentially mediated by UCHL3. Therefore, S100A11 inhibition represents a promising therapeutic strategy for tendon repair.