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WIREs Dev Biol
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Fibrodysplasia ossificans progressiva: a human genetic disorder of extraskeletal bone formation, or—how does one tissue become another?

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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. WIREs Dev Biol 2012, 1:153–165. doi: 10.1002/wdev.9 This article is categorized under: Signaling Pathways > Cell Fate Signaling Vertebrate Organogenesis > Musculoskeletal and Vascular Birth Defects > Organ Anomalies

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Clinical features of fibrodysplasia ossificans progressiva (FOP). The classic clinical phenotype of FOP is characterized by two features: (a) The extensive heterotopic bone formation typical of FOP is seen in a three‐dimensional reconstructed computed tomography (CT) scan of the back of a 12‐year‐old child. Ribbons, sheets, and plates of bone form in extraskeletal connective tissue and fuse the joints of the axial and appendicular skeleton. For comparison, an image of a normal skeleton (back view) can be viewed at http://www.shutterstock.com/pic.mhtml?id=11313556. (b) Radiograph of the feet of a 3‐year‐old child shows symmetrical great toe malformations (the circle indicates the left foot malformation) of metatarsals and proximal phalanges along with microdactyly, fused interphalangeal joints, and hallux valgus deviations at the metatarsophalangeal joints. (Reprinted with permission from Ref 21. Copyright 2006 Nature Publishing Group)

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Heterotopic ossification in FOP. The initial stages of FOP lesion formation involves inflammation and the destruction of connective tissues (a and b), followed by tissue replacement (c and d). Inflammatory and immune cell infiltration (a) is followed by tissue degradation and loss of the skeletal muscle structure (b). Subsequent tissue formation includes fibroproliferation and angiogenesis (c), followed by chondrogenesis and osteogenesis (d) and the formation of heterotopic endochondral bone. (Images are from patient biopsies obtained prior to a diagnosis of FOP. Tissue trauma, including biopsies, can induce FOP lesion formation and therefore are not obtained following diagnosis.) Figure courtesy of Salin Chakkalakal, PhD.

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Generalized schematic of the BMP signaling pathway. Type I and type II BMP receptors span the cell membrane and bind extracellular BMP ligand. Ligand binding to receptor complexes activates signaling through type II receptor phosphorylation of the type I receptor at the glycine–serine (GS) domain. Type I receptor phosphorylation is accompanied by reduced GS binding by proteins, such as FKBP1A, that regulate receptor signaling in the absence of ligand binding. Activated type I receptor phosphorylates cytoplasmic signal transduction proteins such as R‐SMADs and MAPKs, which in turn, directly or indirectly regulate transcription of target genes in the nucleus. (Reprinted with permission from Ref 7. Copyright 2010 Nature Publishing Group)

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Vertebrate Organogenesis > Musculoskeletal and Vascular
Signaling Pathways > Cell Fate Signaling
Birth Defects > Organ Anomalies