Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.
Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.
复制标题
DOI：
10.1172/jci153792
复制
发表时间：
2022-06-15
影响因子：
15.9
通讯作者：
Hatsell, Sarah J.
中科院分区：
文献类型：
--
作者：
Aykul, Senem;Huang, Lily;Wang, Lili;Das, Nanditha M.;Reisman, Sandra;Ray, Yonaton;Zhang, Qian;Rothman, Nyanza;Nannuru, Kalyan C.;Kamat, Vishal;Brydges, Susannah;Troncone, Luca;Johnsen, Laura;Yu, Paul B.;Fazio, Sergio;Lees-Shepard, John;Schutz, Kevin;Murphy, Andrew J.;Economides, Aris N.;Idone, Vincent;Hatsell, Sarah J.
进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，其最令人衰弱的病理是骨骼肌、韧带、肌腱和筋膜的进行性和累积性异位骨化（HO）。FOP是由I型BMP受体基因ACVR 1的突变引起的，这使得ACVR 1能够利用其天然拮抗剂激活素A作为激动性配体。该性质的生理相关性通过以下事实强调：FOP中的HO精确地依赖于激活素A对FOP突变体ACVR 1的激活，该效应通过单克隆抗体治疗抑制抗激活素A来抵消。因此，我们推测阻断配体激活ACVR1的抗ACVR1抗体也应该抑制FOP中的HO，并为这种疾病提供额外的治疗选择。因此，我们产生了抗ACVR1单克隆抗体，其阻断ACVR1通过其配体的激活。令人惊讶的是，在体内，这些抗ACVR 1抗体刺激HO并激活FOP突变型ACVR 1的信号传导。该特性仅限于FOP突变体ACVR 1，并且是由抗ACVR 1抗体介导的ACVR 1二聚化引起的。相反，野生型ACVR1被抗ACVR1抗体抑制。这些结果揭示了FOP突变型ACVR 1的另一特性，并表明抗ACVR 1抗体不应被视为FOP的治疗剂。
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 mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti–activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody–mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.