Heterotopic Ossification: Clinical Features, Basic Researches, and Mechanical Stimulations

Abstract

Heterotopic ossification (HO) is defined as the occurrence of extraskeletal bone in soft tissue. Although this pathological osteogenesis process involves the participation of osteoblasts and osteoclasts during the formation of bone structures, it differs from normal physiological osteogenesis in many features. In this article, the primary characteristics of heterotopic ossification are reviewed from both clinical and basic research perspectives, with a special highlight on the influence of mechanics on heterotopic ossification, which serves an important role in the prophylaxis and treatment of HO.

Keywords: bone; bone formation; heterotopic ossification; mechanical loading; stem cell fate.

FIGURE 1

Hypothesis of Mechanical Stimulation of HO: Mechanical stress initiates osteogenic differentiation of mesenchymal stem cells (MSCs) in soft tissue. Stem cell fate of MSCs shifts from favoring lipogenic cells to osteogenic cells under mechanical loading. According to the published literature about HO, after the mechanical loading, the activations of the YAP/TAZ and mTORC1 pathway enable MSCs to differentiate into osteoblasts, and the decrease in PPARγ expression reduces the differentiation of MSC into adipocytes.

FIGURE 2

Signaling pathway of HO due to mechanical stimulation: Mechanical stimulation through mTORC1 leads to an increase in Sirt1 translocation into the nucleus, followed by a decrease in SOST secretion. SOST can bind to LRP5/6 to inhibit β-catenin. Mechanical loading can also activate Runx2/3 gene expression through YAP/TAZ. Thus mechanical stimulation promotes osteogenic gene expression through mTORC1 and YAP/TAZ. Meanwhile, mechanical stimulation can inhibit PPARγ gene expression through the TGF-β pathway, thereby suppressing lipogenic differentiation. These combined effects lead to a stem cell fate shift.