Macrophage Polarization in Heterotopic Ossification: Inflammation, Osteogenesis, and Emerging Therapeutic Targets

Heterotopic ossification (HO) refers to an abnormal process characterized by the aberrant development of bone within soft tissues, leading to significant impairments in patients' mobility and overall quality of life. Macrophages, as a crucial element of the immune system, are instrumental in the different stages of heterotopic ossification through their dynamic polarization state (pro-inflammatory M1 and anti-inflammatory M2 phenotypes) and secretion of different cytokines. This review explores novel mechanisms of M1 and M2 macrophage-mediated heterotopic ossification, emphasizing the involvement of the inflammatory microenvironment, osteogenic factors, and osteogenic signaling pathways. In addition, we explore promising therapeutic strategies targeting macrophage polarization and function, including agents that modulate the inflammatory microenvironment, such as IL-1 inhibitors, parovastatin, and metformin, as well as agents that affect macrophage osteogenic signaling, such as TGF-βRII-Fc, Galunisertib, and Ruxolitinib. A more comprehensive understanding of these mechanisms may open up new avenues for developing novel approaches to reducing HO in high-risk patients.