Tendon stem/progenitor cells in heterotopic ossification: functional regulation, molecular mechanisms and targeted therapeutic strategies

Heterotopic ossification (HO) is a pathological process in which ectopic bone tissue forms within soft tissues such as tendons, resulting in pain, limited range of motion, and functional disability that reduces the quality of life. In recent years, tendon stem/progenitor cells (TSPCs) have been considered a key cellular source of HO due to their inherent multilineage differentiation potential. This review aims to systematically elaborate on the advances in the functional regulation and mechanisms of TSPCs in HO. Existing evidence (including lineage tracing and clinical studies) indicates that under the stimulation of trauma, inflammation, and other factors, the chondrogenic and osteogenic differentiation of TSPCs are abnormally activated, shifting their fate from tendon repair to ectopic bone formation. This process is centrally regulated by osteochondrogenesis-related signaling pathways such as BMP, as well as inflammatory signaling pathways such as NF-κB. External factors such as mechanical and inflammatory microenvironment also play important stimulatory roles. Based on these mechanisms, drugs and biomaterials targeting the function of TSPCs have shown potential for the prevention and treatment of HO. Future research needs to explore the heterogeneity of TSPCs and the spatiotemporal dynamics of their regulatory networks, providing theoretical support for the clinical translation of therapeutic strategies. The translational potential of this article: Given the critical role of TSPCs in driving heterotopic ossification through aberrant differentiation, targeting these cells represents a highly promising translational strategy. This review details how external stimuli change the local microenvironment and disrupt the signaling networks within TSPCs, shifting their fate from tissue repair to abnormal bone formation. Highlighting the application of pharmacological agents and biomaterials to precisely modulate the behavior of TSPCs supports a crucial shift toward targeted preventative therapies.