Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification

Int J Mol Sci. 2022 Jun 23;23(13):6983. doi: 10.3390/ijms23136983.


The term heterotopic ossification (HO) describes bone formation in tissues where bone is normally not present. Musculoskeletal trauma induces signalling events that in turn trigger cells, probably of mesenchymal origin, to differentiate into bone. The aetiology of HO includes extremely rare but severe, generalised and fatal monogenic forms of the disease; and as a common complex disorder in response to musculoskeletal, neurological or burn trauma. The resulting bone forms through a combination of endochondral and intramembranous ossification, depending on the aetiology, initiating stimulus and affected tissue. Given the heterogeneity of the disease, many cell types and biological pathways have been studied in efforts to find effective therapeutic strategies for the disorder. Cells of mesenchymal, haematopoietic and neuroectodermal lineages have all been implicated in the pathogenesis of HO, and the emerging dominant signalling pathways are thought to occur through the bone morphogenetic proteins (BMP), mammalian target of rapamycin (mTOR), and retinoic acid receptor pathways. Increased understanding of these disease mechanisms has resulted in the emergence of several novel investigational therapeutic avenues, including palovarotene and other retinoic acid receptor agonists and activin A inhibitors that target both canonical and non-canonical signalling downstream of the BMP type 1 receptor. In this article we aim to illustrate the key cellular and molecular mechanisms involved in the pathogenesis of HO and outline recent advances in emerging molecular therapies to treat and prevent HO that have had early success in the monogenic disease and are currently being explored in the common complex forms of HO.

Keywords: Hoxa11+ mesenchymal stromal cells; activin A/ALK2; bone morphogenetic protein; genetics; heterotopic ossification; retinoic acid receptor.

Publication types

  • Review

MeSH terms

  • Bone Morphogenetic Proteins / metabolism
  • Humans
  • Ossification, Heterotopic* / etiology
  • Ossification, Heterotopic* / genetics
  • Osteogenesis
  • Receptors, Retinoic Acid
  • Signal Transduction


  • Bone Morphogenetic Proteins
  • Receptors, Retinoic Acid