TY - JOUR T1 - ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1 JF - bioRxiv DO - 10.1101/2021.07.18.452865 SP - 2021.07.18.452865 AU - Senem Aykul AU - Lily Huang AU - Lili Wang AU - Nanditha Das AU - Sandra Reisman AU - Yonaton Ray AU - Qian Zhang AU - Nyanza Rothman AU - Kalyan C. Nannuru AU - Vishal Kamat AU - Susannah Brydges AU - Luca Troncone AU - Laura Johnsen AU - Paul B. Yu AU - John Lees-Shepard AU - Kevin Schutz AU - Andrew J. Murphy AU - Aris N. Economides AU - Vincent Idone AU - Sarah J. Hatsell Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/19/2021.07.18.452865.abstract N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by amino acid-altering mutations in ACVR1, a type I BMP receptor. The mutations occur in the region encoding the intracellular domain of ACVR1 and bestow FOP-mutant ACVR1 with the neofuction of recognizing Activin A as an agonistic ligand. (In contrast, Activin A antagonizes BMP signaling from wild type ACVR1.) This neofuction is required for HO in FOP as inhibition of Activin A stops the initiation and progression of heterotopic bone lesions in FOP. These results unequivocally demonstrated that HO in FOP is dependent on activation of FOP-mutant ACVR1 by ligand and set the stage to explore ACVR1-blocking antibodies as an additional potential therapeutic for FOP. Surprisingly, ACVR1 antibodies stimulate – rather than inhibit – HO and induce Smad1/5/8 phosphorylation of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1, as signaling by wild type ACVR1 is inhibited by these antibodies, as is trauma-induced HO. These results uncover yet an additional novel property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as a therapeutic strategy for FOP.Competing Interest StatementThe authors have declared no competing interest. ER -