The hypoxic microenvironment: a driving force for heterotopic ossification progression

Heterotopic ossification (HO) refers to the formation of bone tissue outside the normal skeletal system. According to its pathogenesis, HO is divided into hereditary HO and acquired HO. There currently lack effective approaches for HO prevention or treatment. A deep understanding of its pathogenesis will provide promising strategies to prevent and treat HO. Studies have shown that the hypoxia-adaptive microenvironment generated after trauma is a potent stimulus of HO. The hypoxic microenvironment enhances the stability of hypoxia-inducible factor-1α (HIF-1α), which regulates a complex network including bone morphogenetic proteins (BMPs), vascular endothelial growth factor (VEGF), and neuropilin-1 (NRP-1), which are implicated in the formation of ectopic bone. In this review, we summarize the current understanding of the triggering role and underlying molecular mechanisms of the hypoxic microenvironment in the initiation and progression of HO, focusing mainly on HIF-1 and it's influenced genes  BMP, VEGF, and NRP-1. A better understanding of the role of hypoxia in HO unveils novel therapeutic targets for HO that reduce the local hypoxic microenvironment and inhibit HIF-1α activity. Video Abstract. (MP4 52403 kb).