Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification.
Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification.
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DOI：
10.1002/jbmr.4617
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发表时间：
2022-11
影响因子：
6.2
通讯作者：
Goldhamer, David J.
中科院分区：
文献类型：
--
作者：
Yamamoto, Masakazu;Stoessel, Sean J.;Yamamoto, Shoko;Goldhamer, David J.
关键词：
进行性骨化性纤维发育不良（FOP）是一种具有毁灭性的进行性异位骨形成疾病，目前尚无有效的治疗方法。FOP是由受体ACVR1（也称为ALK2）的显性功能获得性突变引起的，这种突变使受体对激活素配体产生不适当的反应。在先前的研究中，我们开发了一种FOP的基因小鼠模型，该模型重现了该疾病的大多数临床特征。在这个模型中，野生型Acvr1等位基因的遗传性缺失极大地加剧了异位骨化，这提示了野生型和突变型受体的化学计量决定疾病严重程度的假设。在这里，我们通过产生条件性过表达人野生型ACVR1的FOP小鼠来验证这个模型。当突变型和野生型受体的表达都靶向Tie2阳性细胞（包括成纤维/脂肪祖细胞，FAPs）时，损伤诱导的异位骨化（HO）在FOP小鼠中被完全阻断。Acvr1 R206H/+小鼠的围产期致死率通过组成性ACVR1过表达得以挽救，并且这些小鼠以预期的孟德尔频率存活至成年。ACVR1的组成性过表达也提供了对自发性骨骼发育异常的保护，并且这些小鼠中损伤诱导的HO的发生率和严重程度显著降低。对培养细胞和体内pSMAD1/5/8信号传导的分析表明，ACVR1过表达通过减少对激活素A的成骨信号传导而在细胞自主发挥作用。我们提出ACVR1过表达通过降低细胞表面含ACVR1（R206H）的信号复合物的丰度，同时增加由野生型ACVR1组成的结合激活素A的非信号复合物的比例来抑制HO。© 2022作者。《骨与矿物质研究杂志》由威利期刊有限责任公司代表美国骨与矿物质研究学会（ASBMR）出版。
Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain‐of‐function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild‐type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild‐type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally overexpress human wild‐type ACVR1. Injury‐induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild‐type receptor were targeted to Tie2‐positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1 R206H/+ mice was rescued by constitutive ACVR1 overexpression, and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive overexpression of ACVR1 also provided protection from spontaneous abnormal skeletogenesis, and the incidence and severity of injury‐induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 overexpression functions cell‐autonomously by reducing osteogenic signaling in response to activin A. We propose that ACVR1 overexpression inhibits HO by decreasing the abundance of ACVR1(R206H)‐containing signaling complexes at the cell surface while increasing the representation of activin‐A‐bound non‐signaling complexes comprised of wild‐type ACVR1. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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影响因子：
5.4
作者：
Heinecke K;Seher A;Schmitz W;Mueller TD;Sebald W;Nickel J
通讯作者：
Nickel J
DOI：
10.1002/jbmr.2820
发表时间：
2016-09
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Chakkalakal SA;Uchibe K;Convente MR;Zhang D;Economides AN;Kaplan FS;Pacifici M;Iwamoto M;Shore EM
通讯作者：
Shore EM
影响因子：
3.5
作者：
Haupt, Julia;Deichsel, Alexandra;Seemann, Petra
通讯作者：
Seemann, Petra
影响因子：
4.1
作者：
Haupt J;Xu M;Shore EM
通讯作者：
Shore EM
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：
Shore, Eileen M.