The effect of timing in the administration of hepatocyte growth factor to modulate BMP-2-induced osteoblast differentiation
The effect of timing in the administration of hepatocyte growth factor to modulate BMP-2-induced osteoblast differentiation
复制标题
DOI：
10.1016/j.biomaterials.2009.10.048
复制
发表时间：
2010-02-01
期刊：
影响因子：
14
通讯作者：
Toyama, Yoshiaki
中科院分区：
文献类型：
--
作者：
Kawaski, Toshiki;Niki, Yasuo;Toyama, Yoshiaki
骨形态发生蛋白（BMP）信号调节剂的开发可能为临床大骨缺损的治疗提供有用的治疗选择。关于肝细胞生长因子 (HGF) 是 BMP 诱导的成骨作用的正调节剂还是负调节剂仍存在争议。这项研究分析了 HGF 的成骨特性，特别是在 BMP-2 诱导的骨形成过程中。使用异位骨形成的小鼠模型，HGF 浸渍的明胶海绵在放射学和组织学上显示 BMP-2 诱导的骨形成显着减少。通过敲低 HGF mRNA 消除内源性 HGF 产生，导致体外 C2C12 成肌细胞 BMP-2 诱导的 ALP 活性上调。相反，添加外源性 HGF 通过 HGF-c-Met 相互作用抑制 BMP-2 诱导的 ALP 活性和小鼠胚胎成纤维细胞 (MEF) 的骨钙素产生。 MEK1/2 抑制剂 U0126 可以挽救 HGF 对 ALP 活性的抑制，表明 HGF 通过激活 ERK1/2 来抑制 BMP-2-Smad 轴。重要的是，在施用BMP-2之前用HGF治疗诱导MEF的细胞增殖，并且不影响随后由BMP-2诱导的成骨细胞分化。 HGF 的作用可能根据间充质干细胞的分化阶段而有所不同，这可以解释之前报道中 HGF 成骨特性的不一致。 HGF 治疗的时机至关重要，应仔细确定，以便 BMP 成功诱导骨形成。 (C) 2009 Elsevier Ltd. 保留所有权利。
Development of bone morphogenetic protein (BMP) signaling modulators may provide useful therapeutic options for the treatment of large bony defects in clinical settings. Controversy remains over whether hepatocyte growth factor (HGF) is a positive or negative modulator of BMP-induced osteogenesis. This study analyzed osteogenic properties of HGF, particularly during BMP-2-induced bone formation. Using a mouse model of ectopic bone formation, HGF-impregnated gelatin sponges displayed significantly reduced bone formation induced by BMP-2, both radiologically and histologically. Abrogation of endogenous HGF production by knockdown of HGF mRNA resulted in upregulation of BMP-2-induced ALP activity for C2C12 myoblasts in vitro. In contrast, addition of exogenous HGF inhibited BMP-2-induced ALP activity and osteocalcin production by mouse embryonic fibroblasts (MEFs) through HGF-c-Met interactions. Inhibition of ALP activity by HGF was rescued by U0126, a MEK1/2 inhibitor, indicating that HGF suppresses the BMP-2-Smad axis via activation of ERK1/2. importantly, treatment with HGF prior to administration of BMP-2 induced cellular proliferation of MEFs and did not influence subsequent osteoblast differentiation induced by BMP-2. The effects of HGF may differ according to the differentiation stage of mesenchymal stem cells, which would explain the inconsistencies seen in osteogenic properties of HGF in previous reports. The timing of HGF treatment is critical and should be carefully determined for successful induction of bone formation by BMPs. (C) 2009 Elsevier Ltd. All rights reserved.