Fibrodysplasia ossificans progressiva (FOP): A disorder of extraskeletal endochondral ossification

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder in which extraskeletal bone forms in soft connective tissues, initiating during childhood and continuing throughout adult life. This heterotopic bone is qualitatively normal and forms through endochondral ossification. Episodes of bone formation often occur in response to injury. In addition to heterotopic ossification, FOP is associated with altered skeletal development, the most characteristic of which is malformation of the great toes. All FOP patients that we have examined carry mutations in ACVR1 , the gene encoding the ALK2 BMP type I receptor. Most patients are heterozygous for the same mutation in codon 206 (R206H) in the GS domain of the receptor. This ACVR1/ALK2 mutation induces mild constitutive activation of the BMP pathway and enhances signaling in response to BMP. The identification of the causative gene in FOP, together with the development of in vivo and in vitro models for heterotopic ossification and mesenchymal cell differentiation, is providing opportunities to understand the cellular and molecular mechanisms that regulate chondrogenesis and osteogenesis and control the pathological induction of heterotopic bone formation. This knowledge will lead to novel approaches to modulate BMP signaling and bone formation and to the development of treatments for FOP and other disorders of bone and cartilage.