Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification.
Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification.
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DOI：
10.1002/stem.1633
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发表时间：
2014-05
期刊：
影响因子：
5.2
通讯作者：
Shore, Eileen M.
中科院分区：
文献类型：
--
作者：
Culbert, Andria L.;Chakkalakal, Salin A.;Theosmy, Edwin G.;Brennan, Tracy A.;Kaplan, Frederick S.;Shore, Eileen M.
关键词：
骨形态发生蛋白（BMP）信号是软骨分化和软骨内骨化的关键调节因子。ALK 2（一种I型BMP受体）中的功能获得性突变导致衰弱性疾病进行性骨化性纤维发育不良（FOP），并导致软结缔组织内进行性异位（异位）软骨内骨化。在这里，我们使用小鼠间充质祖细胞，研究在软骨分化和异位软骨内骨化（HEO）的Alk 2的贡献。评价Alk 2 R206 H/+（功能获得）、Alk 2CKO（功能丧失）和野生型小鼠胚胎成纤维细胞的软骨形成潜力。在Alk 2 R206 H/+细胞中，软骨形成分化加速，部分原因是对BMP配体的敏感性增强。在体内，Alk 2 R206 H/+细胞启动了稳健的HEO并募集野生型细胞贡献。尽管其他I型BMP受体（Alk 3和Alk 6）的表达，软骨形成的Alk 2CKO细胞严重受损的情况下，Alk 2在早期分化。因此，Alk 2是软骨形成的直接调节剂，并介导祖细胞的软骨形成定型。这些数据证实，FOP患者中ALK 2功能获得性突变的至少一种效应是增强软骨形成分化，这支持异位软骨内骨的形成。这确立了ALK 2在损伤形成的早期软骨形成阶段作为合理的治疗靶点，用于预防FOP和其他病症中的异位骨形成。
Bone morphogenetic protein (BMP) signaling is a critical regulator of cartilage differentiation and endochondral ossification. Gain-of-function mutations in ALK2, a type I BMP receptor, cause the debilitating disorder fibrodysplasia ossificans progressiva (FOP) and result in progressive heterotopic (extraskeletal) endochondral ossification within soft connective tissues. Here, we used murine mesenchymal progenitor cells to investigate the contribution of Alk2 during chondrogenic differentiation and heterotopic endochondral ossification (HEO). Alk2R206H/+ (gain-of-function), Alk2CKO (loss-of-function), and wild-type mouse embryonic fibroblasts were evaluated for chondrogenic potential. Chondrogenic differentiation was accelerated in Alk2R206H/+ cells, due in part to enhanced sensitivity to BMP ligand. In vivo, Alk2R206H/+ cells initiated robust HEO and recruited wild-type cell contribution. Despite expression of other type I BMP receptors (Alk3 and Alk6), chondrogenesis of Alk2CKO cells was severely impaired by absence of Alk2 during early differentiation. Alk2 is therefore a direct regulator of cartilage formation and mediates chondrogenic commitment of progenitor cells. These data establish that at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone. This establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions.
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条件永生化小鼠胚胎成纤维细胞保留增殖活性而不影响多能分化潜能
影响因子：
3.7
作者：
Huang E;Bi Y;Jiang W;Luo X;Yang K;Gao JL;Gao Y;Luo Q;Shi Q;Kim SH;Liu X;Li M;Hu N;Liu H;Cui J;Zhang W;Li R;Chen X;Shen J;Kong Y;Zhang J;Wang J;Luo J;He BC;Wang H;Reid RR;Luu HH;Haydon RC;Yang L;He TC
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影响因子：
2.6
作者：
CREMIN, B;CONNOR, JM;BEIGHTON, P
通讯作者：
BEIGHTON, P
DOI：
10.2106/00004623-200312000-00010
发表时间：
2003-12-01
影响因子：
5.3
作者：
Glaser, DL;Economides, AN;Shore, EM
通讯作者：
Shore, EM
DOI：
10.1016/b978-0-12-387829-8.00024-x
发表时间：
2013-01-01
期刊：
GENETICS OF BONE BIOLOGY AND SKELETAL DISEASE
影响因子：
--
作者：
Culbert, Andria L.;Chakkalakal, Salin A.;Shore, Eileen M.
通讯作者：
Shore, Eileen M.
影响因子：
7
作者：
Lefebvre, V;Behringer, RR;de Crombrugghe, B
通讯作者：
de Crombrugghe, B