Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation.
Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation.
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DOI：
10.2741/1912
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发表时间：
2006-05
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通讯作者：
Aiko Nakashima;Masato Tamura
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作者：
Aiko Nakashima;Masato Tamura
在骨重建过程中，骨骼结缔组织的降解至少部分地受到基质金属蛋白酶（MMP）和基质金属蛋白酶组织抑制剂（TIMP）（它们的天然抑制剂）之间的平衡的调节。最近，Wnt信号通路已被证明在骨形成的调节中起着至关重要的作用。在这里，我们研究了Wnt信号和功能性串扰与骨形态发生蛋白（BMP）-2在多能C2 C12细胞中的MMPs，TIMPs和骨基质蛋白的mRNA表达的潜在作用。为了评估Wnt信号传导的功能贡献，我们产生了稳定过表达Wnt 3a或Wnt 5a的C2 C12细胞系，然后用BMP-2处理这些细胞24小时。在这些培养物中，MMP-13 mRNA表达在Wnt 3a过表达的C2 C12（Wnt 3a-C2 C12）细胞中由BMP-2诱导，但在Wnt 5a过表达的C2 C12（Wnt 5a-C2 C12）细胞或载体转染的C2 C12细胞中不诱导。BMP-2作用12 h后，MMP-13 mRNA表达增强，并持续至48 h。观察到这些效应呈剂量依赖性。MMP-13的酶活性也通过添加BMP-2在Wnt 3a-C2 C12细胞中诱导。然而，膜1型基质金属蛋白酶（MT 1-MMP）和MMP-2的mRNA表达不受Wnt 3a或BMP-2。BMP-2可抑制Wnt 3a-C2 C12细胞TIMP-1 mRNA的表达，但对Wnt 5a-C2 C12细胞TIMP-1 mRNA的表达无影响。我们的研究结果表明，MMP-13和TIMP-1的表达是由Wnt信号结合BMP-2在成骨细胞分化的调节，这种信号可能部分介导MMP-13和TIMP-1的生产过程中骨形成和/或重塑。
During bone remodeling, degradation of skeletal connective tissue is regulated, at least in part, by the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs), their natural inhibitors. Recently, the Wnt signaling pathway has been demonstrated to play a crucial role in the regulation of bone formation. Here, we investigated a potential role for Wnt signaling and functional cross-talk with bone morphogenetic protein (BMP)-2 in mRNA expression of MMPs, TIMPs and bone matrix proteins in pluripotent C2C12 cells. To assess the functional contribution of Wnt signaling, we have generated C2C12 cell lines stably over-expressing Wnt3a or Wnt5a, and then treated these cells with BMP-2 for 24 h. In these cultures, MMP-13 mRNA expression was induced by BMP-2 in Wnt3a over-expressing C2C12 (Wnt3a-C2C12) cells but not in either Wnt5a over-expressing C2C12 (Wnt5a-C2C12) cells or vehicle-transfected C2C12 cells. MMP-13 mRNA was induced in these cells by addition of BMP-2 for 12 h and the enhancement lasted up to 48 h. These effects were observed in a dose-dependent manner. Enzymatic activity of MMP-13 also induced in Wnt3a-C2C12 cells by addition of BMP-2. However, membrane type-1 matrix metalloproteinase (MT1-MMP) and MMP-2 mRNA expression was not affected by either Wnt3a or BMP-2. In contrast, TIMP-1 mRNA expression was suppressed by BMP-2 in Wnt3a-C2C12 cells but not in Wnt5a-C2C12 cells. Our results show that expression of MMP-13 and TIMP-1 is regulated by Wnt signaling combined with BMP-2 in osteoblastic differentiation, and this signaling may in part mediate MMP-13 and TIMP-1 production during bone formation and/or remodeling.