title: Fibrodysplasia ossificans progressiva: a human genetic disorder of extraskeletal bone formation, or--how does one tissue become another?
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which de novo osteogenesis—a developmental process occurring during embryonic skeletal formation—is induced aberrantly and progressively beginning during early childhood in soft connective tissues. Episodic initiation of spontaneous bone-forming lesions occurs over time, affecting a generally predictable sequence of body locations following a pattern similar to that of the developing embryonic skeleton. The heterotopic (extraskeletal) bone formation in FOP can also be induced by connective tissue injury. At the tissue level, an initial tissue degradation phase is followed by a tissue formation phase during which soft connective tissues are replaced by bone tissue through endochondral osteogenesis. This extraskeletal bone is physiologically normal and develops through the same series of tissue differentiation events that occur during normal embryonic skeletal development. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation. In addition to postnatal heterotopic ossification, FOP patients show specific malformations of skeletal elements indicating effects on bone formation during embryonic development as well. Nearly all cases of FOP are caused by the identical mutation in the ACVR1 gene that causes a single amino acid substitution, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1 (formerly known as ALK2). This mutation causes mild constitutive activation of the BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation, providing opportunities to investigate previously unrecognized functions for this receptor during tissue development and homeostasis.
authors.affiliation: Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. shore@mail.med.upenn.edu
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D009221:Myositis Ossificans / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D009999:Ossification, Heterotopic / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed
chemical_list: C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I