Hatsell Sarah J, Idone Vincent, Wolken Dana M Alessi, Huang Lily, Kim Hyon J, Wang Lili, Wen Xialing, Nannuru Kalyan C, Jimenez Johanna, Xie Liqin, Das Nanditha, Makhoul Genevieve, Chernomorsky Rostislav, D'Ambrosio David, Corpina Richard A, Schoenherr Christopher J, Feeley Kieran, Yu Paul B, Yancopoulos George D, Murphy Andrew J, Economides Aris N
Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Brigham and Women's Hospital, 20 Shattuck Street, Thorn Biosciences 1203, Boston, MA 02115, USA.
Sci Transl Med. 2015 Sep 2;7(303):303ra137. doi: 10.1126/scitranslmed.aac4358.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1(R206H)) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1(R206H) mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1(R206H) causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.
进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，其特征是间歇性地出现过度的异位骨化（HO），即骨骼肌异常转化为位置不当但组织学上正常的骨骼。这种异位骨化导致渐进性运动障碍，产生灾难性后果，包括窒息死亡。FOP是由I型骨形态发生蛋白（BMP）受体ACVR1的细胞内结构域发生突变引起的；最常见的突变是将精氨酸206变为组氨酸（ACVR1(R206H)），人们认为这种突变会因受体过度活跃而导致不适当的骨形成。我们意外地发现，这种突变使ACVR1对激活素家族的配体产生反应，激活素通常通过ACVR1拮抗BMP信号，但正常情况下不能诱导骨形成。为了在体内测试这一发现的意义，我们对小鼠进行基因改造，使其携带Acvr1(R206H)突变。由于组成型表达Acvr1[R206H]的小鼠在出生时死亡，我们针对这种突变构建了一种基因人源化的条件性敲入模型。当诱导Acvr1[R206H]表达时，小鼠出现了类似于FOP的异位骨化；在这个FOP小鼠模型中，注射激活素A也能引发异位骨化，但野生型对照小鼠则不会。最后，广泛作用的BMP阻滞剂以及一种针对激活素A的全人源抗体能够阻止异位骨化。我们的结果表明，ACVR1(R206H)通过获得对通常具有拮抗作用的配体激活素A的反应性而导致FOP，这表明在一个基因精确的FOP模型中，这种配体对于驱动异位骨化是必要且充分的；因此，我们针对激活素A的人源抗体代表了一种治疗FOP的潜在方法。
