Interaction of Tmem119 and the bone morphogenetic protein pathway in the commitment of myoblastic into osteoblastic cells.
Interaction of Tmem119 and the bone morphogenetic protein pathway in the commitment of myoblastic into osteoblastic cells.
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DOI：
10.1016/j.bone.2012.04.017
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发表时间：
2012-07
期刊：
影响因子：
4.1
通讯作者：
Ken-ichiro Tanaka;Y. Inoue;G. Hendy;L. Canaff;T. Katagiri;R. Kitazawa;T. Komori;T. Sugimoto;S. Seino;H. Kaji
中科院分区：
文献类型：
--
作者：
Ken-ichiro Tanaka;Y. Inoue;G. Hendy;L. Canaff;T. Katagiri;R. Kitazawa;T. Komori;T. Sugimoto;S. Seino;H. Kaji
骨形态发生蛋白（BMP）对于骨再生至关重要，并可诱导体内异位骨形成。 BMP 1 型受体、激活素 A 1 型受体/激活素样激酶 2 (ACVR1/ALK2) 的组成型激活突变 (R206H) 是进行性骨化性纤维发育不良 (FOP) 的分子发病机制的基础，其中肌肉组织中发生异位骨化。在本研究中，我们对稳定空载体和 ALK2(R206H) 转染的小鼠成肌细胞 C2C12 细胞进行了比较 DNA 微阵列分析。鉴定出 40 个基因，其表达在实验组中比对照组增加了 >3.5 倍。骨形成相关因子 Tmem119 也包含在该组中。稳定表达 Tmem119 的 C2C12 细胞中成骨细胞分化标志物和矿化增强。成肌细胞向肌管的分化受到抑制，但向软骨细胞的分化几乎不受影响。即使没有外源 BMP-2，BMP-2 信号分子 Smad1/5 的转录活性也会增加。内源性 BMP-2 水平与 Tmem119 水平呈正相关。 BMP-2/4 中和抗体和 Dorsomorphin（一种 ALK2 抑制剂）可拮抗 Tmem119 增强的碱性磷酸酶 (ALP) 水平。 Tmem119 siRNA 在 C2C12 细胞中拮抗 BMP-2 诱导的 ALP 和骨钙素，但不拮抗 Runx2 和 Osterix mRNA。总之，成肌细胞中 FOP 相关的组成型激活 ALK2 突变导致 Tmem119 水平升高。数据显示，Tmem119促进成肌细胞分化为成骨细胞，并且与BMP信号通路的相互作用可能发生在成肌细胞中Runx2和Osterix的下游。 Tmem119 可能在肌祖细胞向成骨细胞谱系的定型中发挥关键作用。
Bone morphogenetic proteins (BMPs) are critical for bone regeneration and induce ectopic bone formation in vivo. The constitutively activating mutation (R206H) of the BMP type 1 receptor, activin A type 1 receptor/activin-like kinase 2 (ACVR1/ALK2), underlies the molecular pathogenesis of fibrodysplasia ossificans progressiva (FOP) in which heterotopic ossification occurs in muscle tissue. In the present study, we performed a comparative DNA microarray analysis between stable empty vector- and ALK2(R206H)-transfected mouse myoblastic C2C12 cells. Forty genes were identified whose expression was increased >3.5 times in the experimental group versus the control. The bone formation-related factor, Tmem119, was included in this group. Osteoblast differentiation markers and mineralization were enhanced in C2C12 cells stably expressing Tmem119. Differentiation of myoblastic cells into myotubes was suppressed but differentiation into chondrocytes was little affected. Transcriptional activity of the BMP-2 signaling molecules, Smad1/5, was increased even in the absence of exogenous BMP-2. Endogenous BMP-2 levels positively correlated with Tmem119 levels. A BMP-2/4 neutralizing antibody and dorsomorphin, an ALK2 inhibitor, antagonized Tmem119-enhanced alkaline phosphatase (ALP) levels. Tmem119 siRNA antagonized the BMP-2-induced ALP and osteocalcin, but not Runx2 and Osterix, mRNAs, in C2C12 cells. In conclusion, Tmem119 levels were increased by the FOP-associated constitutively activating ALK2 mutation in myoblasts. The data show that Tmem119 promotes the differentiation of myoblasts into osteoblasts and the interaction with the BMP signaling pathway likely occurs downstream of Runx2 and Osterix in myoblasts. Tmem119 may play a critical role in the commitment of myoprogenitor cells to the osteoblast lineage.