The Role of Collagen Matrix in the Development and Progression of Heterotopic Ossification in Tendon and Its Biological Mechanisms

As the primary force-transmitting structure in the musculoskeletal system, tendons are susceptible to collagen fiber disorganization and microenvironmental alterations following mechanical overload or traumatic injury. The aberrant mineralization cascade ultimately culminates in heterotopic ossification (HO), wherein heterotopic bone forms through dysregulated osteogenic processes. Current therapeutic paradigms for tendon HO remain palliative rather than curative, underscoring critical knowledge gaps in its etiopathogenesis. Therefore, the present review paper systematically examines emerging evidence on the synergistic interplay between damaged collagen architecture and ionic/protein microenvironment changes in driving HO progression, with particular emphasis on how collagen ultrastructural defects serve as mineralization templates through stereochemical nucleation, and microenvironmental ionic/protein alterations that amplify osteochondrogenic differentiation. The mechanistic framework of HO elucidated in the present paper would further contribute to novel strategies development for the prevention and treatment of pathological mineralization in tendon.