The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling

Abstract

The ability of mature organisms to stabilize phenotypes has enormous selective advantage across all phyla, but the mechanisms have been largely unexplored. Individuals with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of progressive heterotopic ossification, undergo a pathological metamorphosis in which one normal tissue is transformed into another through a highly regulated process of tissue destruction and phenotype reassignment. This disabling metamorphosis is mediated by the FOP metamorphogene, which encodes a mutant bone morphogenetic protein (BMP) type I receptor that exhibits mild constitutive activity during development and severe episodic dysregulation postnatally. The discovery of the FOP metamorphogene reveals a highly conserved target for drug development and identifies a fundamental defect in the BMP signaling pathway that when triggered by injury and inflammation transforms one tissue into another.

Figure 1. The FOP metamorphogene and its major phenotypes

The FOP metamorphogene encodes a type I BMP receptor (ACVR1/ALK2; R206H) that dysregulates BMP signaling and accounts for all of the congenital and postnatal features of FOP including congenital malformations of the great toes, heterotopic endochondral ossification, and ectopic skeletogenesis in characteristic anatomic patterns.

Figure 2. Working model of heterotopic ossification in FOP

Injury to skeletal muscle and connective tissues leads to lymphocyte and monocyte invasion, macrophage and mast cell activation, tissue hypoxia, and upregulation of inflammatory cytokines and osteogenic factors that recruit vascular progenitor cells to form the heterotopic anlagen. Hypoxia and pro-inflammatory cytokines contribute to the Tie2+ angiogenic response. Hypoxia-related changes may further sensitize vascular progenitor cells in which the FOP metamorphogene is expressed. The inflammatory response to muscle injury, the ambient hypoxia, the presence of the promiscuously active FOP metamorphogene in vascular progenitor cells, and the cross-talk between cells of the innate and adaptive immune system stimulate the induction and propagation of an ectopic skeletal element. CTPs, connective tissue progenitor cells; HSC, hematopoietic stem cells; T, T-cells; B, B-cells; MA, mast cells; FP, fibroproliferative cells; CB, chondroblasts; OB, osteoblasts; PGE₂, prostaglandin E₂; TNFα, tumor necrosis factor-alpha; blue lines, hematopoietic-derived pathways; brown lines, CTP-derived pathways; blunt-end lines signify inhibitory pathways; arrows signify stimulatory pathways. (Modified from Lounev et al. J Bone Joint Surg Am 91: 652-663, 2009)