CCN3 increases BMP-4 expression and bone mineralization in osteoblasts
CCN3 increases BMP-4 expression and bone mineralization in osteoblasts
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DOI：
10.1002/jcp.22991
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发表时间：
2012-06-01
影响因子：
5.6
通讯作者：
Tang, Chih-Hsin
中科院分区：
文献类型：
--
作者：
Tan, Tzu-Wei;Huang, Yuan-Lin;Tang, Chih-Hsin
肾母细胞瘤过度表达 (NOV) 基因，也称为 CCN3，调节骨骼间充质细胞的分化。骨形态发生蛋白（BMP）在成骨细胞分化和骨形成中发挥重要作用，但CCN3对培养的成骨细胞中BMP表达和骨形成的影响尚不清楚。在这里，我们发现CCN3增加了培养的成骨细胞中BMP-4的表达和骨结节的形成。 a5 beta 1 和 av beta 5 整合素的单克隆抗体，以及整合素连接激酶 (ILK)、p38 和 JNK 的抑制剂，均能抑制 CCN3 诱导的骨结节形成和成骨细胞的 BMP-4 上调。 CCN3 刺激增加了 ILK 的激酶活性以及 p38 和 JNK 的磷酸化。激活蛋白 1 (AP-1) 抑制剂还抑制 CCN3 增强的骨结节形成和 BMP-4 表达。此外，CCN3诱导的c-Jun易位到细胞核中，以及c-Jun与BMP-4启动子上的AP-1元件的结合都被ILK、p38和JNK级联的特异性抑制剂抑制。综上所述，我们的结果证明CCN3增强成骨细胞中BMP-4的表达和骨结节的形成，并且整合素受体、ILK、p38、JNK和AP-1信号通路可能参与其中。 J.细胞。生理学。 227: 25312541, 2012。(c) 2011 Wiley 期刊公司。
The nephroblastoma overexpressed (NOV) gene, also called CCN3, regulates differentiation of skeletal mesenchymal cells. Bone morphogenetic proteins (BMPs) play important roles in osteoblast differentiation and bone formation, but the effects of CCN3 on BMP expression and bone formation in cultured osteoblasts are largely unknown. Here we found that CCN3 increased BMP-4 expression and bone nodule formation in cultured osteoblast. Monoclonal antibodies for a5 beta 1 and av beta 5 integrins, and inhibitors of integrin-linked kinase (ILK), p38, and JNK, all inhibited CCN3-induced bone nodule formation and BMP-4 up-regulation of osteoblasts. CCN3 stimulation increased the kinase activity of ILK and phosphorylation of p38 and JNK. Inhibitors of activator protein-1 (AP-1) also suppressed bone nodule formation and BMP-4 expression enhanced by CCN3. Moreover, CCN3-induced c-Jun translocation into the nucleus, and the binding of c-Jun to the AP-1 element on the BMP-4 promoter were both inhibited by specific inhibitors of the ILK, p38, and JNK cascades. Taken together, our results provide evidence that CCN3 enhances BMP-4 expression and bone nodule formation in osteoblasts, and that the integrin receptor, ILK, p38, JNK, and AP-1 signaling pathways may be involved. J. Cell. Physiol. 227: 25312541, 2012. (c) 2011 Wiley Periodicals, Inc.