Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification

Abstract

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.

Atrophic macules containing mesenchymal cells are precursor lesions of osteoma cutis in Albright hereditary osteodystrophy

“…On histopathology, the bone tissue contains marrow elements. Bone is frequently surrounded by hypercellular mesenchymal tissue, but no cartilage is seen, thus indicating intramembranous bone formation 1 …”

“…Bone is frequently surrounded by hypercellular mesenchymal tissue, but no cartilage is seen, thus indicating intramembranous bone formation. 1 We have not been able to identify in the literature any report of lesions in the pre-ossification stage in AHO. We believe that knowledge of the histopathology features presented here may aid for a very early diagnosis of AHO even in newborns.…”

“…Primary osteoma cutis is a rare condition of intramembranous ossification as a result of differentiation of mesenchymal stem cells into bone without previous cartilage formation. 1 It is a hallmark of several genetic conditions appearing under different phenotypes, including Albright's hereditary osteodystrophy (AHO), osteomatosis cutis, progressive osseous heteroplasia (POH), and plate-like osteoma cutis. 2 There is considerable overlap between these conditions in relation to their skin and endocrinological manifestations.…”

The Kinesin Gene KIF26B Modulates the Severity of Post-Traumatic Heterotopic Ossification

“…The dominant pathways in HO include BMP, mTOR and RAR signalling. A more detailed overview of our current understanding of the molecular biology of HO is given in a recent review in this journal [ 10 ].…”

The role of miRNA and lncRNA in heterotopic ossification pathogenesis

“…Experimental approaches directly targeting molecular and signaling processes have been tested in vivo, in animal models, and in humans [ 86 ]. Human studies focus on the severe form of HO to FOP.…”