Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling.
Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling.
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DOI：
10.1002/jbmr.2848
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发表时间：
2016-09
影响因子：
6.2
通讯作者：
Pignolo, Robert J.
中科院分区：
文献类型：
--
作者：
Wang, Haitao;Lindborg, Carter;Lounev, Vitali;Kim, Jung-Hoon;McCarrick-Walmsley, Ruth;Xu, Meiqi;Mangiavini, Laura;Groppe, Jay C.;Shore, Eileen M.;Schipani, Ernestina;Kaplan, Frederick S.;Pignolo, Robert J.
缺氧和炎症与异位软骨内骨化（HEO）的间歇性诱导有关;然而，其分子机制尚不清楚。HIF-1α整合了细胞对缺氧和炎症的反应，是调节HEO的主要候选者。我们研究了缺氧和HIF-1α在进行性骨化性纤维发育不良（FOP）中的作用，FOP是人类最严重的HEO形式。我们发现HIF-1α通过Rabaptin 5（RABEP 1）介导的激活素A受体I型（ACVR 1）（一种BMP受体）在FOP患者的缺氧结缔组织祖细胞的内体区室中的保留增加典型骨形态发生蛋白（BMP）信号传导的强度和持续时间。我们进一步表明，人类和小鼠模型中的早期炎性FOP病变明显缺氧，通过遗传或药理学手段抑制HIF-1α可使人FOP细胞中的典型BMP信号传导恢复至常氧水平，并显著降低组成性活性Acvr 1 Q207 D/+ FOP小鼠模型中的HEO。因此，炎症和细胞氧敏感机制，调节细胞内滞留的突变BMP受体决定，部分，其病理活性FOP。我们的研究提供了一个关键的洞察，以前未被认识到的作用，HIF-1α在缺氧放大的BMP信号和在情节诱导的HEO在FOP，并进一步确定HIF-1α作为一个治疗目标FOP和可能的非遗传形式的HEO。
Hypoxia and inflammation are implicated in the episodic induction of heterotopic endochondral ossification (HEO); however, the molecular mechanisms are unknown. HIF-1α integrates the cellular response to both hypoxia and inflammation and is a prime candidate for regulating HEO. We investigated the role of hypoxia and HIF-1α in fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of HEO in humans. We found that HIF-1α increases the intensity and duration of canonical bone morphogenetic protein (BMP) signaling through Rabaptin 5 (RABEP1)-mediated retention of Activin A receptor, type I (ACVR1), a BMP receptor, in the endosomal compartment of hypoxic connective tissue progenitor cells from patients with FOP. We further show that early inflammatory FOP lesions in humans and in a mouse model are markedly hypoxic, and inhibition of HIF-1α by genetic or pharmacologic means restores canonical BMP signaling to normoxic levels in human FOP cells and profoundly reduces HEO in a constitutively active Acvr1Q207D/+ mouse model of FOP. Thus, an inflammation and cellular oxygen-sensing mechanism that modulates intracellular retention of a mutant BMP receptor determines, in part, its pathologic activity in FOP. Our study provides critical insight into a previously unrecognized role of HIF-1α in the hypoxic amplification of BMP signaling and in the episodic induction of HEO in FOP, and further identifies HIF-1α as a therapeutic target for FOP and perhaps non-genetic forms of HEO.
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影响因子：
3.5
作者：
Emerling, Brooke M.;Viollet, Benoit;Chandel, Navdeep S.
通讯作者：
Chandel, Navdeep S.
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
影响因子：
7
作者：
Gelse, K.;Muehle, C.;Schneider, H.
通讯作者：
Schneider, H.
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：
13
作者：
Kaplan, Frederick S.;Pignolo, Robert J.;Shore, Eileen M.
通讯作者：
Shore, Eileen M.