ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.
ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.
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DOI：
10.1126/scitranslmed.aac4358
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发表时间：
2015-09-02
影响因子：
17.1
通讯作者：
Economides AN
中科院分区：
文献类型：
--
作者：
Hatsell SJ;Idone V;Wolken DM;Huang L;Kim HJ;Wang L;Wen X;Nannuru KC;Jimenez J;Xie L;Das N;Makhoul G;Chernomorsky R;D'Ambrosio D;Corpina RA;Schoenherr CJ;Feeley K;Yu PB;Yancopoulos GD;Murphy AJ;Economides AN
纤维肿瘤的纤维增生性（FOP）是一种罕见的遗传疾病，其特征是发作的异位骨化骨化（HO），从而使骨骼肌完全转化为放错了位置，但在组织学上，这种HO导致了与灾难性后果的渐进性。 FOP是由I型BMP（骨形态发生蛋白）受体ACVR1的细胞内结构域的突变引起的最常见的突变将精氨酸206变为组氨酸（ACVR1R206H），并被认为是由于受体过度活性而导致的不适当的骨形成。但是通常无法诱导骨形成。突变。由于构成型的ACVR1 [R206H]在围产期中死亡，因此在ACVR1 [R206H]表达时产生了一个有条件的条件性敲门模型，因此ho ho ho ho ho ho ho ho ho ho ho ho op op op op op也可能在此FOP的小鼠模型中触发A活化素A，但在野生型对照中不触发。对激活素A的完全人类抗体。我们的结果表明，ACVR1R206H通过获得对正常拮抗的配体激活素A的响应来引起FOP，这表明这种配体是必需的，足以在遗传准确的FOP模型中驱动HO；激活素A代表FOP的潜在治疗方法。
在纤维化发育不全的患者中，引起疾病的突变会改变ACVR1受体的配体反应谱，以使其被正常拮抗的配体activin A激活。
解释骨过度生长
纤维肿瘤浮肿（FOP）是一种罕见但致命的遗传状况，在骨形态发生的蛋白质受体ACVR1中，代替正常软组织（例如肌肉和韧带）而导致粘合结构的生长。接收者的活动触发不适当的骨骼。与损伤有关的因子激活素，这可能解释了该疾病的一些难题方面。
在培养细胞中表达的突变的ACVR1受体对激活素及其天然配体的骨形态发生蛋白有反应。骨化，如FOP，对于异型骨化，接收器需要内源性配体激活素的刺激。被植入动物。
最后，作者证实，激活素A是治疗FOP的潜在治疗靶点：携带突变接收器的动物，这些动物也接受了激活素A的单克隆抗体治疗，即使在引入后6周后，也没有显示出异质骨化突变引起的配体特异性变化是疾病的异常原因对组织的损伤或创伤 - 一种诱导高浓度激活素的情况。
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 (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 Acvr1R206H 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 ACVR1R206H 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. In patients with fibrodysplasia ossificans progressiva, the disease-causing mutation changes the ligand response profile of the ACVR1 receptor so that it is activated by the normally antagonistic ligand activin A. Explaining bone overgrowth Fibrodysplasia ossificans progressiva (FOP) is a rare, but deadly, genetic condition that causes growth of bony structures in place of normally soft tissues such as muscle and ligaments. The causal mutation, in the bone morphogenetic protein receptor ACVR1, has been thought to boost the receptor’s activity, triggering inappropriate bone formation. Hatsell et al. suggest that it works instead by a different mode of action—acquiring the ability to respond to the injury-related factor activin, which may explain some of the puzzling aspects of the disease. The mutated ACVR1 receptor, expressed in cultured cells, responded to activin as well as to its natural ligand, bone morphogenetic protein. When the mutated gene was engineered to be expressed in adult mice (to avoid its perinatal lethal effects), the animals developed heterotopic ossification, as in FOP. Unexpectedly, for heterotypic ossification, the receptor required stimulation by the endogenous ligand activin. Small sponges soaked with activin ossified after they were implanted into the animals. Normally, activin blocks binding of the ACVR1 receptor by its natural ligand bone morphogenetic protein-2. Finally, the authors confirmed that activin A is a potential therapeutic target for the treatment of FOP: Animals carrying the mutated receptor that were also treated with a monoclonal antibody to activin A did not show heterotopic ossification, even as long as 6 weeks after introduction of the mutation. A mutation-induced ligand specificity change is an unusual cause of disease, but this mechanism may explain why the ossification in FOP patients is triggered by injury or trauma to tissues—a situation that induces high concentrations of activin.
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影响因子：
3.7
作者：
Pignolo RJ;Shore EM;Kaplan FS
通讯作者：
Kaplan FS
DOI：
10.1186/s12964-015-0104-z
发表时间：
2015-06-06
期刊：
Cell communication and signaling : CCS
影响因子：
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作者：
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Holien T
DOI：
10.2106/00004623-200312000-00010
发表时间：
2003-12-01
影响因子：
5.3
作者：
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通讯作者：
Shore, EM
影响因子：
4
作者：
Lowery, Jonathan W.;Intini, Giuseppe;Rosen, Vicki
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影响因子：
5.2
作者：
Culbert, Andria L.;Chakkalakal, Salin A.;Theosmy, Edwin G.;Brennan, Tracy A.;Kaplan, Frederick S.;Shore, Eileen M.
通讯作者：
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