Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva.
Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva.
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DOI：
10.1038/s41467-018-02872-2
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发表时间：
2018-02-02
影响因子：
16.6
通讯作者：
Goldhamer DJ
中科院分区：
文献类型：
--
作者：
Lees-Shepard JB;Yamamoto M;Biswas AA;Stoessel SJ;Nicholas SE;Cogswell CA;Devarakonda PM;Schneider MJ Jr;Cummins SM;Legendre NP;Yamamoto S;Kaartinen V;Hunter JW;Goldhamer DJ
进行性骨化性纤维发育不良（FOP）是一种罕见的常染色体显性遗传疾病，其特征是进行性和严重致残的异位骨化（HO）。在这里，我们表明，在精确的FOP遗传小鼠模型（Acvr 1 tnR 206 H）中，脂肪/成脂祖细胞（FAP）是HO的主要起源细胞。将致病的I型骨形态发生蛋白（BMP）受体ACVR 1（R206 H）靶向表达至FAP，概括了在FOP患者中观察到的HO的全谱。表达ACVR 1（R206 H）的FAP（而非野生型FAP）响应激活素配体激活成骨信号传导。野生型Acvr 1等位基因的条件性丧失显著加剧FAP-定向HO，表明突变体和野生型ACVR 1受体复合物竞争激活素配体或II型BMP受体结合伴侣。最后，激活素A的全身抑制完全阻断HO并恢复移植的Acvr 1 R206 H/+ FAP的野生型样行为。了解驱动HO的细胞可能有助于开发细胞特异性治疗方法，以抑制FOP中的灾难性骨形成。进行性骨化性纤维发育不良是一种以异位骨化为特征的严重疾病，由ACVR 1突变引起。在这里，作者表明，突变体ACVR 1在脂肪/成脂祖细胞中的表达再现了疾病进展，并且这可以通过全身抑制小鼠中的激活素A来停止。
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1tnR206H). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP. Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
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影响因子：
4.6
作者：
Agarwal S;Loder S;Cholok D;Peterson J;Li J;Fireman D;Breuler C;Hsieh HS;Ranganathan K;Hwang C;Drake J;Li S;Chan CK;Longaker MT;Levi B
通讯作者：
Levi B
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：
2.5
作者：
Alva, JA;Zovein, AC;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
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.
影响因子：
17.1
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
通讯作者：
Economides AN