Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva
Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva
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DOI：
10.1074/jbc.m801681200
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发表时间：
2009-03-13
影响因子：
4.8
通讯作者：
Katagiri, Takenobu
中科院分区：
文献类型：
--
作者：
Fukuda, Toru;Kohda, Masakazu;Katagiri, Takenobu
进行性骨化纤维发育不良（FOP）是一种罕见的常染色体显性遗传病，以先天性大脚趾畸形和肌肉组织进行性异位骨形成为特征。最近，在FOP患者中发现了一个涉及骨形态发生蛋白（BMP） I型受体ALK2中单个氨基酸替换的突变。我们在此报告，在19名日本散发性FOP患者中观察到相同的突变R206H。这种突变受体ALK2（R206H）在没有配体结合的情况下激活BMP信号。此外，肌肉损伤后，Smad1和Smad5的表达上调。携带Smad1或Smad5的ALK2（R206H）诱导成骨细胞分化，可被Smad7或dorsomorphin抑制。综上所述，这些发现表明FOP中的异位骨形成可能是由Smad1或Smad5组成性激活的BMP受体信号诱导的。Smad7的基因转移或dorsomorphin抑制I型受体可能是阻断ALK2（R206H）在FOP中诱导的活性的策略。
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.