The role of endothelial-mesenchymal transition in heterotopic ossification

Abstract

Heterotopic ossification (HO) is a process by which bone forms in soft tissues, in response to injury, inflammation, or genetic disease. This usually occurs by initial cartilage formation, followed by endochondral ossification. A rare disease called fibrodysplasia ossificans progressiva (FOP) allows this mechanism to be induced by a combination of genetic mutation and acute inflammatory responses. FOP patients experience progressive HO throughout their lifetime and form an ectopic skeleton. Recent studies on FOP have suggested that heterotopic cartilage and bone is of endothelial origin. Vascular endothelial cells differentiate into skeletal cells through a mesenchymal stem cell intermediate that is generated by endothelial-mesenchymal transition (EndMT). Local inflammatory signals and/or other changes in the tissue microenvironment mediate the differentiation of endothelial-derived mesenchymal stem cells into chondrocytes and osteoblasts to induce HO. We discuss the current evidence for the endothelial contribution to heterotopic bone formation.

Fig. 1

A schematic diagram of the proposed mechanism of EndMT-induced heterotopic ossification. Endothelial cells from capillary blood vessels in muscle tissue undergo EndMT in response to inflammation and an activating mutation in ALK2 in patients with FOP. Cytokines such as BMP2, BMP4, or TGF-β2 can mimic the effects of the ALK2 mutation, while proteins such as BMP7 and VEGF, or a chemical inhibitor of ALK2 like dorsomorphin, can prevent EndMT. These endothelial-derived mesenchymal stem-like cells (MSCs) differentiate into chondrocytes and osteoblasts in response to inflammatory signals. Chondrogenesis occurs first, followed by endochondral ossification.