• Identification of fibroblast-derived BMP5 as a paracrine factor driving mesenchymal stem cell differentiation into myofibroblasts and tendon adhesion. • Mechanistic demonstration that paclitaxel (PTX) suppresses BMP5 expression through inhibition of the HIF-1α pathway, preventing MSC-to-myofibroblast transition. • Development of two PLA-based delivery systems: physically blended PTX (PLB) and polymer–drug conjugated PTX (PLC) membranes. • PLC membranes achieve controlled release, reduced cytotoxicity, and superior anti-adhesion efficacy in vivo. • Provides both mechanistic insights into tendon fibrosis and a translational biomaterial-based therapeutic strategy for adhesion prevention. Tendon adhesion following injury remains a major clinical challenge, primarily driven by excessive fibrosis and aberrant cellular differentiation. Here, we identify fibroblast-derived bone morphogenetic protein 5 (BMP5) as a key paracrine signal that promotes mesenchymal stromal cell (MSC) differentiation into myofibroblasts, thereby exacerbating adhesion formation. Mechanistically, we show that paclitaxel (PTX) suppresses BMP5 expression in fibroblasts via inhibition of the HIF-1α pathway, thus blocking MSC-to-myofibroblast transition. To achieve sustained local delivery, we developed polylactic acid based membranes (PLA) incorporating PTX in either a blended (PLB) or conjugated (PLC) form, with PLC demonstrating controlled release, reduced cytotoxicity, and superior anti-adhesion efficacy. Collectively, our results reveal a BMP5-centered fibroblast–MSC axis as a key driver of tendon adhesion and establish PTX-loaded PLC membranes as a mechanism-based therapeutic strategy.
Wang et al. (Sun,) studied this question.