Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 — the ability to recognize activin A as an agonist with bone morphogenic protein–like signaling that leads to heterotopic ossification (HO). These findings are supported by the efficacy of anti–activin A antibodies in preventing HO in FOP mice. This surprising story continues in companion papers in this issue of the JCI . Aykul et al. and Lees-Shepard et al. independently found that antibodies against ACVR1, which were being developed as potential therapeutics for FOP, instead caused HO in FOP mice. While this unexpected finding may be the clinical final act for such antibodies, it provides another twist in the unique and evolving FOP story.

Lysosomal degradation of ACVR1-Activin complexes negatively regulates signaling of Activins and Bone Morphogenetic Proteins

“…Our findings have implications for therapeutic approaches targeting ACVR1 signaling in FOP and other indications. Various approaches are under investigation 36 , including inhibition of Activin A 15 , inhibition of ACVR1 kinase [37][38][39] , inhibition of ACVR1 using blocking antibodies 4,16,[40][41][42] , and siRNA-mediated reduction of ACVR1 expression 43 . Our findings predict that at the molecular level these approaches will have different outcomes.…”