Contemporary perspectives on heterotopic ossification

Abstract

Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.

Figure 1. HO induces reactivation of developmental programs found in bone.

Bone development in traumatic and genetic forms of HO is initiated by a range of inflammatory responses and recapitulation of developmental bone biology, via both predictable patterns of direct mesenchymal progenitor cell (MPC) differentiation into bone-forming osteoblasts (intramembranous ossification, top progress bar) and the deposition of cartilagenous scaffold via chondroblasts and subsequent infiltration and differentiation of osteoblasts (endochondral ossification, bottom progress bar). These yield robust formation of bony lesions typified in the appendicular skeleton in traumatic HO versus the axial skeleton in genetic forms, i.e., fibrodysplasia ossificans progressiva (FOP) (bottom).

Figure 2. Cell signaling pathways in bone formation.

The postinflammatory component of HO formation continues to echo patterns found in normal bone development, including cascades triggered by members of the TGF-β superfamily (TGF-β, activin/inhibins, and BMP) as well as Wnt, Shh, and retinoic acid (RA). These ligand-receptor complexes propagate signaling by cognate secondary messengers including SMAD2/3, SMAD1/5/8, β-catenin, and Smo/Gαs, and RAR-MAPK. These signaling cascades yield transcriptional changes that regulate chondrogenic and osteogenic differentiation.

Figure 3. Extrainflammatory pathways that regulate HO formation.

Contemporary work has extensively expanded the understanding of regulatory effects on the HO program. Extending from existing work investigating developmental bone biology and fracture healing physiology, several independent niches have been found to impact the formation of ectopic bone, particularly in the setting of posttraumatic HO. Representative topics include vascular and hypoxia signaling pathways involving VEGFA/VEGFR1, Hif1α, endothelium, and perivascular cells (top left and top right); nerve and perineural structures along with associated neurotrophic factors, e.g., NGF and receptor TrkA (bottom left); and the effect of mechanical deformation and forces exerted on progenitor cells residing/migrating through stromal substrates that yield downstream activation through interaction of integrins and FAK, YAP, and TAZ (bottom right).