Molecular and cellular mechanisms of heterotopic ossification

Abstract

Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients' lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone.

Fig. 1

An overview of the mechanisms of heterotopic ossification. Trauma to muscle tissue stimulates sensory neurons to release Substance P, which will promote mast cell degranulation and subsequent inflammation in the area of injury. Myeloid cells and lymphocytes invade the injured tissue and promote skeletal myocyte cell death. These immune cells also release cytokines such as TGF-β2 and BMP4, which cause the vascular endothelial cells to undergo endothelial-mesenchymal transition (EndMT) to form multipotent mesenchymal stem-like cells (MSCs). Inflammatory signals and the muscle microenvironment foster these MSCs to differentiate into chondrocytes and osteoblasts to form heterotopic lesions of cartilage and bone. Resident skeletal muscle MSCs and Glast-positive progenitor cells may also contribute to the formation of the ectopic skeletal tissue.