Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva – How Does One Tissue Become Another?

Abstract

The development and maintenance of tissues and organ systems depend on precise coordination of cellular events and mechanisms. During embryonic development, the induction of bone formation is spatially and temporally regulated to specify the skeletal elements. After birth, new bone formation is normally limited to regeneration during fracture repair, a process that is also precisely regulated.Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which extensive and progressive heterotopic ossification – the formation of bone outside of the normal skeleton – occurs in soft connective tissues such as skeletal muscle. At birth, there is usually little indication of the disease, except for a characteristic malformation of the great toes. However during early childhood, episodes of bone formation that are frequently associated with swelling and inflammation begin within soft tissues. In most patients examined to date, FOP is caused by a single nucleotide change in the BMP type I receptor ACVR1 (Activin A receptor, type 1; alias, ALK2) that causes enhanced pathway activation. All patients with a classic clinical presentation of the disease possess a recurrent heterozygous c.617G>A (R206H) mutation.Heterotopic ossification in FOP frequently forms in response to tissue injury, although also develops in the absence of overt tissue trauma. Within the tissue, heterotopic bone formation in FOP patients progresses through well‐described changes in affected tissue: initial catabolic events are followed by an anabolic stage and formation of endochondral bone. In vivo mouse models have been instrumental in providing a more detailed understanding of the tissue, cellular, and molecular impact of the ACVR1 R206H mutation and the structural changes in the soft connective tissues that are transitioning to cartilage and bone. In response to injury, initial steps of wound healing in mutant tissue appear to be normal, including an early immune response that leads to tissue degradation and removal of damaged tissue. However this tissue repair trajectory rapidly diverges and, instead of repairing and regenerating the injured muscle tissue, ectopic cartilage and bone are formed. Our investigations of these events are providing a more detailed understanding of the tissue, cellular, and molecular impact of the ACVR1 R206H mutation and of the mechanisms that regulate tissue maintenance, repair, and regeneration.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.