Conserved signaling pathways underlying heterotopic ossification

Abstract

Heterotopic ossification (HO), a serious disorder of extra-skeletal bone formation, occurs as a common complication of trauma or in rare genetic disorders. Many conserved signaling pathways have been implicated in HO; however, the exact underlying molecular mechanisms for many forms of HO are still unclear. The emerging picture is that dysregulation of bone morphogenetic protein (BMP) signaling plays a central role in the process, but that other conserved signaling pathways, such as Hedgehog (HH), Wnt/β-catenin and Fibroblast growth factors (FGF), are also involved, either through cross-talk with BMP signaling or through other independent mechanisms. Deep understanding of the conserved signaling pathways is necessary for the effective prevention and treatment of HO. In this review, we update and integrate recent progress in this area. Hopefully, our discussion will point to novel promising, druggable loci for further translational research and successful clinical applications.

Keywords: Bone morphogenetic protein (BMP); Conserved signaling pathways; Fibroblast growth factor (FGF); Fibrodysplasia ossificans progressiva (FOP); Hedgehog (HH); Heterotopic ossification (HO); Transforming growth factor β (TGF-β); Wnt/β-catenin.

Fig. 1

Intergrated working model. We propose that BMP signaling cascade through Smad and Mapk pathways is the major regulator of the pathological osteogenic process. Nevertheless, cross-talking at different levels between BMP, other conserved signal pathways could lead to synegetic effects, competitive inhibition, and/or feedback regulations. Together, they form an overwhelmingly complicate network.