日期：2015-09-06 期刊：Science
DOI：
10.1126/scitranslmed.aac4358 作者：Aris N. Economides
文字说明: 在进行性骨性纤维化发育不良小鼠模型的后肢区域中的软组织骨异常形成，这一过程被称作异位骨化。应用黄色假色彩影像处理来凸显异位骨。
对于罹患一种会将肌肉转变成为骨头的罕见的、且无法治疗的骨病的患者来说，一种疗法可能让这些患者最终得到治疗的现实又接近了一步。一项新的研究揭示了一种生长因子是如何促生该病的，它给这种目前让人束手无策的疾病提供了一种新的治疗标靶。进行性骨化性纤维发育异常(FOP)有时被称作“石人综合征”，它是一种致命的遗传性疾病，该病会令肌肉和软组织逐渐变成骨头，从而形成一种令身体无法活动的额外骨骼。该病是由于控制骨和肌肉发育的一种受体ACVR1发生突变所致。这些突变被认为将这种受体的活性推至超速档，从而导致异常的骨生长。是否有某种分子与ACVR1结合以触发疾病仍然是未知的。为了弄清真相，Sarah Hatsell和同事设计了一个FOP模型，在该模型中，他们能精确地控制成年小鼠中ACVR1突变的表达。他们发现，该变异受体会被激活素-A异常激活;激活素-A是一种生长因子，它通常会阻断ACVR1的活性。当被植入到小鼠体内时，浸有该生长因子的胶原蛋白海绵会转变成为骨头，从而促生该病。由研究人员研发的一种激活素-A特异性人类抗体可终止小鼠体内的骨形成长达6个星期。该生长因子常常是在因应损伤和炎症时由免疫系统分泌的，它或能帮助解释FOP患者体内的骨生长为什么常常会由组织肿胀或炎症所触发。这些发现将激活素-A推出作为FOP中炎症与骨形成之间的一个缺失的环节，而激活素-A特异性抗体或是针对这种灾难性疾病的一种有前途的治疗方法。
原文链接：ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A
原文摘要:
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), wherby 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 (ACVR1R206H) 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 ACVR1R206Hmutation. 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 thatACVR1R206Hcauses 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.
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