Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons

Abstract

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVRI/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP. The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.

Figure 1

Symptomatic Treatment of FOP (Adapted from: The International Clinical Consortium on FOP. The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations. Clin Proc Intl Clin Consort FOP 2011; 4:1-100)

Figure 2. RAR Gamma Agonists Derail Heterotopic Endochondral Ossification

Tissue metamorphosis in HEO involves two major phases - a catabolic (destructive) phase of acute inflammation and tissue destruction followed by an anabolic (formative) phase of tissue neogenesis involving the formation of a transient cartilaginous scaffold, and its replacement with mature heterotopic bone. A key feature of HEO is the formation of a bridging cartilaginous scaffold that is under control of the BMP and Wnt/β-catenin signaling pathways. RARγ agonists inhibit BMP signaling and promote Wnt/β-catenin signaling in cells that build the cartilaginous scaffold, disrupting the bridge and de-railing HEO. RARγ agonists can re-program MSCs to a non-HEO soft tissue fate, thus effectively backing-up the train into the station if it has not yet reached the bridge. [MSC (mesenchymal stem cells); FP (fibroproliferative cells); CP (cartilage progenitor cells); CH (chondrocytes); OB (osteoblasts). Arrows in pathways signify stimulation; blunt-ended lines signify inhibition. Arrows along the railroad track between cell types indicate stages of progression of HEO. The length of the train on the track indicates the well-established finding that contiguous stages of HEO occur simultaneously in different anatomic areas of the lesion. The time in days for each stage is an estimate, and varies with the age of the patient or the animal model studied. (Adapted from: Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med 2011; 17:420-421).

Figure 3. Neuroinflam0matory Pathways in Heterotopic Ossification

This schematic depicts the major neuroinflammatory pathways described in the accompanying text. PG/BK= prostaglandins/bradykinins, inflammatory molecules that are released at sites of local soft tissue injury. TRPV1= Transient Receptor Potential Vanilloid 1, a calcium/magnesium (Ca⁺⁺/Mg⁺⁺) cation channel receptor expressed at the terminals of primary sensory neurons. PPTA=preprotachykinin, the gene that makes Substance P (SP) and several other inflammatory neuropeptides. DRG= dorsal root ganglia, clusters of primary sensory nerve cells (located near the spinal cord) at each spinal level, the site where Substance P is made, and the site from where pain and temperature signals enter the central nervous system. ACVR1 (R206H)=the FOP mutation. The increased BMP signaling that results from FOP (and likely from other sporadic forms of HO) sensitizes the TRPV cation channel receptor and also likely increases the synthesis of NK1R. NK1R=neurokinin 1 receptor (the cell surface receptor for Substance P), expressed on many inflammatory cells, most notably mast cells and macrophages (M). A subgroup of endothelial cells is converted to mesenchymal stem cells (MSCs) in an endothelial to mesenchymal transition (EMT) under the influence of inflammation and the FOP gene. MSCs transform into cartilage and bone cells by a process of heterotopic endochondral ossification (HEO), a process negatively regulated by RAR_γ. Green=nerve fibers. Blue=mast cells and macrophages. Dashed lines=transport of chemicals or neurotransmitters. Cupped ends=receptors. Arrows=stimulation. Blunt ended lines=inhibition. ? =Possible pathways.