Heterotopic bone induction via BMP signaling: Potential therapeutic targets for fibrodysplasia ossificans progressiva

Abstract

More than 50years ago, Marshal M. Urist detected "heterotopic bone-inducing activity" in demineralized bone matrix. This unique activity was referred to as "bone morphogenetic protein (BMP)" because it was sensitive to trypsin digestion. Purification of the bone-inducing activity from demineralized bone matrix using a bone-inducing assay in vivo indicated that the original "BMP" consisted of a mixture of new members of the transforming growth factor-β (TGF-β) family. The establishment of new in vitro assay systems that reflect the bone-inducing activity of BMPs in vivo have revealed the functional receptors and downstream effectors of BMPs. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic bone formation in soft tissues similar to the event induced by the transplantation of BMPs in skeletal muscle. In patients with FOP, genetic mutations have been identified in the ACVR1 gene, which encodes the BMP receptor ALK2. The mutations in ALK2 associated with FOP are hypersensitive to type II receptor kinases. Recently, activin A, a non-osteogenic member of the TGF-β family, was identified as the ligand of the mutant ALK2 in FOP, and various types of signaling inhibitors for mutant ALK2 are currently under development to establish effective treatments for FOP.

Keywords: Bone morphogenetic proteins; Heterotopic bone formation; Interstitial mesenchymal cells; Smad proteins; Transmembrane serine/threonine kinase receptors.