PDZRN3 negatively regulates BMP-2-induced osteoblast differentiation through inhibition of Wnt signaling.
PDZRN3 negatively regulates BMP-2-induced osteoblast differentiation through inhibition of Wnt signaling.
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DOI：
10.1091/mbc.e10-02-0117
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发表时间：
2010-09-15
影响因子：
3.3
通讯作者：
Inui M
中科院分区：
文献类型：
--
作者：
Honda T;Yamamoto H;Ishii A;Inui M
PDZRN3是含PDZ结构域的RING finger蛋白家族成员，通过抑制Wnt -β-catenin信号传导，在bmp -2诱导的C2C12小鼠间充质祖细胞成骨分化的负反馈调控中发挥重要作用。PDZRN3是含有PDZ结构域的RING finger蛋白家族的成员。我们之前的研究表明，PDZRN3对于C2C12小鼠间充质祖细胞分化为肌管至关重要。除了肌管外，间充质祖细胞还分化成成骨细胞、软骨细胞和脂肪细胞，我们现在已经研究了PDZRN3在C2C12细胞分化成成骨细胞中的潜在作用。在低血清培养基中暴露于骨形态发生蛋白(BMP)-2诱导成骨细胞分化后，C2C12细胞中PDZRN3丰度增加。通过RNA干扰去除C2C12细胞中的PDZRN3，可显著增强bmp -2诱导的碱性磷酸酶（ALP）活性上调。Dkk1是一种Wnt信号的抑制剂，可以通过PDZRN3缺失显著减弱bmp -2诱导的ALP活性的增强。PDZRN3的缺失也促进了Wnta3a对ALP活性的上调。此外，在pdzrn3缺失的细胞中，Wnt3a诱导的LRP6的表达和磷酸化以及Wnt3a诱导的β-catenin细胞质丰度的增加都得到了增强。这些结果表明，PDZRN3通过抑制Wnt -β-catenin信号通路，在bmp -2诱导的C2C12细胞成骨分化的负反馈调控中发挥重要作用。
PDZRN3, a member of the PDZ domain–containing RING finger family of proteins plays an important role in negative feedback control of BMP-2–induced osteoblast differentiation in C2C12 mouse mesenchymal progenitor cells through inhibition of Wnt–β-catenin signaling. PDZRN3 is a member of the PDZ domain–containing RING finger family of proteins. We previously showed that PDZRN3 is essential for the differentiation of C2C12 mouse mesenchymal progenitor cells into myotubes. Mesenchymal progenitor cells differentiate into osteoblasts, chondrocytes, and adipocytes in addition to myotubes, and we have now examined the potential role of PDZRN3 in the differentiation of C2C12 cells into osteoblasts. The abundance of PDZRN3 in C2C12 cells was increased after the induction of osteoblast differentiation by exposure to bone morphogenetic protein (BMP)-2 in low-serum medium. Depletion of PDZRN3 in C2C12 cells by RNA interference resulted in marked enhancement of the BMP-2–induced up-regulation of alkaline phosphatase (ALP) activity. Dkk1, an inhibitor of Wnt signaling, markedly attenuated the enhancement of the BMP-2–induced increase in ALP activity by PDZRN3 depletion. The up-regulation of ALP activity by Wnta3a was also promoted by depletion of PDZRN3. Furthermore, the expression and Wnt3a-induced phosphorylation of LRP6 as well as the increase in the cytosolic abundance of β-catenin induced by Wnt3a were potentiated in PDZRN3-depleted cells. These results indicate that PDZRN3 plays an important role in negative feedback control of BMP-2–induced osteoblast differentiation in C2C12 cells through inhibition of Wnt–β-catenin signaling.