Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP)

Abstract

Metamorphosis, the transformation of one normal tissue or organ system into another, is a biological process rarely studied in higher vertebrates or mammals, but exemplified pathologically by the extremely disabling autosomal dominant disorder fibrodysplasia ossificans progressiva (FOP). The recurrent single nucleotide missense mutation in the gene encoding activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein type I receptor that causes skeletal metamorphosis in all classically affected individuals worldwide, is the first identified human metamorphogene. Physiological studies of this metamorphogene are beginning to provide deep insight into a highly conserved signaling pathway that regulates tissue stability following morphogenesis, and that when damaged at a highly specific locus (c.617G > A; R206H), and triggered by an inflammatory stimulus permits the renegade metamorphosis of normal functioning connective tissue into a highly ramified skeleton of heterotopic bone. A comprehensive understanding of the process of skeletal metamorphosis, as revealed by the rare condition FOP, will lead to the development of more effective treatments for FOP and, possibly, for more common disorders of skeletal metamorphosis.

Fig. 1

Characteristic clinical features of fibrodysplasia ossificans progressiva (FOP). a Extensive heterotopic bone formation typical of FOP is seen by three-dimensional reconstructed computed tomography (CT scan) of the back of a 12-year-old child. b Anteroposterior radiograph of the feet of a 3-year-old child shows symmetrical great toe malformations. [Originally published in Shore EM, et al. (2006) Nat Genet 38:525–527. Copyright held by the authors]

Fig. 2

Hypothetical schema of bone morphogenetic protein (BMP) signaling in FOP cells. [Adapted from Kaplan FS, et al (2008) Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol, in press.] In control cells (A), in the absence of ligand, the Smad/Smurf-FKBP12 (SM-FKBP12) complex binds ACVR1 (a BMP type I receptor) and prevents its promiscuous phosphorylation by the constitutively active type II BMP receptor (not shown). SM-FKBP12 also promotes ubiquitin-associated degradation of ACVR1 in the absence of ligand, thus maintaining low steady-state levels of ACVR1 at the cell membrane. Following ligand binding in control cells (B), SM-FKBP12 inhibition is released, thus allowing the constitutively active BMP type II receptor (not shown) to phosphorylate ACVR1 and promote SMAD1, −5, −8 phosphorylation and downstream BMP signaling. In FOP cells, SM-FKBP12 does not bind appropriately to the mutant receptor [ACVR1 (R206)]. Thus, inhibition of BMP signaling is impaired in the absence of ligand, and basal leakiness of BMP signaling occurs (C). Additionally, because the SM-FKBP12 complex cannot properly target the mutant ACVR1 (R206H) receptor for ubiquitin-associated degradation, ACVR1 might be expected to accumulate at the cell surface. Thus, in the presence of ligand (D), hyper-responsive BMP signaling might be predicted to occur. SM-FKBP12, Smad/Smurf-FKBP12 complex; arrows, signaling promoted; (by FOP mutation); open cups, extracellular ligand-binding domain of ACVR1; filled-in circles, BMP; filled-in circles inside of open cups, BMP ligand binding to ACVR1

Fig. 3

Hypothetical approaches to prevention of skeletal metamorphosis in FOP. Four approaches to prevention of skeletal metamorphosis in FOP are diagrammed and include blocking the putative inflammatory trigger (gun), blocking the signal transduction pathway [using extracellular inhibitors, monoclonal antibodies (MAbs) against the renegade receptor, inhibitory RNA (siRNA) against the mutant receptor RNA, and signal transduction inhibitors (STIs)], blocking the repetitive connective tissue progenitor (CTP) cells that transduce the promiscuous signal, or blocking/altering the permissive microenvironmental niche. EC, extracellular

Fig. 4

Hypothetical model of skeletal metamorphosis in fibrodysplasia ossificans progressiva. (Adapted from Kaplan FS, et al. (2007) Morphogen receptor genes and metamorphogens: skeleton keys to the metamorphosis. Ann N Y Acad Sci 1116:113–133 [38].) PGs, prostaglandins; pO₂, tissue oxygen tension; HIF, hypoxia-inducing factor; CTPs, connective tissue progenitor cells; HSC, hematopoietic stem cells; T, T cells; B, B cells; Mo, monocytes; MA, mast cells; IL-1β, interleukin-1β; IL-6, interleukin 6; TGF-β, transforming growth factor-beta; straight arrows, progression; wavy arrows, influence