Recent Topics in Fibrodysplasia Ossificans Progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease that is characterized by the formation of heterotopic bone tissues in soft tissues, such as skeletal muscle, ligament, and tendon. It is difficult to remove such heterotopic bones via internal medicine or invasive procedures. The identification of activin A receptor, type I (ACVR1)/ALK2 gene mutations associated with FOP has allowed the genetic diagnosis of FOP. The ACVR1/ALK2 gene encodes the ALK2 protein, which is a transmembrane kinase receptor in the transforming growth factor-β family. The relevant mutations activate intracellular signaling in vitro and induce heterotopic bone formation in vivo. Activin A is a potential ligand that activates mutant ALK2 but not wild-type ALK2. Various types of small chemical and biological inhibitors of ALK2 signaling have been developed to establish treatments for FOP. Some of these are in clinical trials in patients with FOP.

Keywords: Heterotopic; Osteogenesis; Receptors; Transforming growth factor beta.

Fig. 1. Schematic representation of the relationship between the activin A receptor, type I (ACVR1)/ALK2 gene, complementary DNA (cDNA) and protein. The ACVR1/ALK2 gene consist of 9 coding exons (Ex.) (black boxes). The ACVR1/ALK2 cDNA (1,530 bp) encodes a protein with 509 amino acids (a. a.). Mutations associated with fibrodysplasia ossificans progressiva are shown in the figure. The positions of the mutations in the cDNA and protein are indicated by numbers that begin from the adenine of the first ATG codon and Met residue, respectively. TGA, stop codon; SP, signal peptide; TM, transmembrane domain; GS, glycine/serine-rich domain; Ser/Thr kinase, serine/threonine kinase domain.

Fig. 2. Schematic representation of signal transduction by ALK2 in response to ligand binding. ALK2 binds to a transforming growth factor-β family ligand, such as bone morphogenetic protein 6 (BMP6), BMP7, and BMP9, and acts as a type I receptor in co-operation with one of the type II receptors (BMP receptor type II [BMPR-II], activin receptor type IIA [ActR-IIA], and activin receptor type IIB [ActR-IIB]). Antagonists, such as follistatin, noggin, and chordin, directly bind to the ligand and prevent it from binding to receptors. Type II receptors are constitutively active kinases that phosphorylate the glycine/serine-rich domain (GS) domain of ALK2 to activate kinase activity. Activated ALK2 phosphorylates downstream substrates, such as Smad1, Smad5, and Smad8/9, and then binds to specific DNA sequences to regulate the transcription of its target genes. Ser/Thr, serine/threonine; P, phosphorylation; FKBP12, 12 kDa FK506-binding protein; Id1, inhibitor of DNA binding 1; BIT-1, BMP-inducible transcript-1.