Promiscuous signaling of ligands via mutant ALK2 in fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disorder characterized by successive heterotopic bone formation, for which at present there is no therapy. Mutations in the bone morphogenetic protein (BMP) type I receptor Activin receptor-like kinase 2 (ACVR1/ALK2) are the main trigger for FOP and inflammation is thought to be the secondary hit. The single nucleotide mutation at position 617 in the cDNA ALK2 sequence, which is found in 98% of FOP patients, results in a R206H change in the intracellular juxtamembrane region of ALK2. Previous studies had revealed that this mutation perturbs the interaction with the negative regulator FKBP12, thereby sensitising cells expressing this mutant receptor to BMPs, which are potent inducers of cartilage and bone formation. Recently, however, a twist in the underlying mechanism of FOP was revealed. Mutant ALK2 was found to respond to Activin-A, whereas wild type ALK2 function is inhibited by Activin-A. The latter cytokine is induced locally upon tissue damage and inflammation. Moreover, therapeutic targeting of Activin-A was found to inhibit heterotopic ossification in a mutant ALK2 knock-in mouse model that is highly reminiscent to human FOP. This review will focus on these latest surprising findings and discuss the implication for treatment of FOP patients.