PKC signaling inhibits osteogenic differentiation through the regulation of Msx2 function
PKC signaling inhibits osteogenic differentiation through the regulation of Msx2 function
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DOI：
10.1016/j.bbamcr.2012.05.018
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发表时间：
2012-08-01
影响因子：
5.1
通讯作者：
Lee, Kwang-Youl
中科院分区：
文献类型：
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作者：
Jeong, Hyung Min;Jin, Yun-Hye;Lee, Kwang-Youl
蛋白激酶 C (PKC) 信号传导调节成骨细胞分化，但对其下游效应器知之甚少。我们检查了调节 PKC 活性对成骨转录因子的影响，发现 Msx2 的蛋白水平受到影响。 Msx2 由 BMP 等成骨信号诱导，在骨形成和成骨细胞分化中发挥关键作用。在这里，我们研究了 PKC 信号在调节 Msx2 功能中的作用。我们发现抑制 PKC 信号传导可增强 BMP2 刺激的 C2C12 细胞的成骨分化。使用 PKC 活性抑制剂或激酶缺陷 (KD)、显性失活突变体 PKC 亚型的过度表达进行治疗，可显着降低 Msx2 蛋白的水平。几种 PKC 同工型（α、β、δ 和 zeta）与 Msx2 相互作用，并且 PKC 在 Thr135 和 Thr141 处磷酸化 Msx2。 Msx2 抑制成骨转录因子 Runx2 的转录活性，并且这种抑制可通过抑制 PKC 活性或过度表达 KD 突变体 PKC 亚型来缓解。此外，PKC延长了Msx2蛋白的半衰期。这些结果表明 PKC 信号传导至少部分通过 Msx2 的调节来调节成骨细胞分化。 (C) 2012 Elsevier B.V. 保留所有权利。
Protein kinase C (PKC) signaling regulates osteoblast differentiation, but little is known about its downstream effectors. We examined the effect of modulating PKC activity on osteogenic transcription factors and found that the protein level of Msx2 is affected. Msx2 is induced by osteogenic signals such as BMPs and it plays critical roles in bone formation and osteoblast differentiation. Here, we examined the role of PKC signaling in regulating the function of Msx2. We found that the inhibition of PKC signaling enhances osteogenic differentiation in BMP2-stimulated C2C12 cells. Treatment with inhibitors of PKC activity or overexpression of kinase-defective (KD), dominant-negative mutant PKC isoforms strongly reduced the level of Msx2 protein. Several PKC isoforms (alpha, beta, delta, and zeta) interacted with Msx2, and PKC beta phosphorylated Msx2 at Thr135 and Thr141. Msx2 repressed the transcriptional activity of the osteogenic transcription factor Runx2, and this repression was relieved by inhibition of PKC activity or overexpression of the KD mutant PKC isoforms. In addition, PKC prolonged the half-life of Msx2 protein. These results suggest that PKC signaling modulates osteoblast differentiation, at least in part, through the regulation of Msx2. (C) 2012 Elsevier B.V. All rights reserved.