Fibrodysplasia Ossificans Progressiva: Evolving Insights from a Rare Disease

摘要

Fibrodysplasia ossificans progressiva (FOP), an autosomal dominant genetic disorder is the most disabling form of heterotopic ossification known to mankind. FOP is characterized by anterior-patterning malformations of the great toes and by progressive induction of endochondral osteogenesis at ectopic sites. Recombinant human bone morphogenetic protein 4 (BMP4), a potent osteogenic morphogen, can induce the entire developmental program of endochondral osteogenesis at an ectopic site in a manner identical to that seen in FOP. BMP4 mRNA and protein are uniquely over-expressed in lymphocytes and lesional cells from patients who have FOP, and preliminary findings suggest that a defect in the BMP4 pathway in FOP cells severely limits their ability to express BMP antagonists in response to a BMP4 stimulus. The BMP4 gene is not mutated in FOP, and the BMP4 locus has recently been excluded from linkage to the condition. These data strongly suggest that the primary defect in FOP is not in the BMP4 gene, but in a component of the BMP4 pathway or interacting pathway that leads to over-expression of BMP4 and misregulation of BMP4 antagonist expression. A more complete understanding of the molecular genetics and pathophysiology of FOP will provide valuable insight into the molecular mechanisms that regulate the induction of osteogenesis and will permit a more rational approach to devising effective treatments for FOP and related disorders.