Interactions between FGF21 and BMP-2 in osteogenesis
Interactions between FGF21 and BMP-2 in osteogenesis
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DOI：
10.1016/j.bbrc.2013.02.019
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发表时间：
2013-03-22
影响因子：
3.1
通讯作者：
Haudenschild, Dominik R.
中科院分区：
文献类型：
--
作者：
Ishida, Kazunari;Haudenschild, Dominik R.
与生活方式相关的疾病正在增加，创造治疗此类疾病的创新药物的挑战是医学科学研究的主要焦点。成纤维细胞生长因子 21 (FGF21) 是一种强大的葡萄糖和脂质代谢调节剂，是一种已进入 2 型糖尿病和肥胖症临床试验的创新候选药物。由这种与生活方式相关的条件引起的骨质脆弱和骨折愈合受损也是一个日益严重的问题。骨形态发生蛋白 (BMP) 是众所周知的成骨生长因子，BMP-2 用于在困难的临床情况下增强骨形成。尽管 FGF21 和 BMP-2 之间的相互作用仍然未知，但 FGF 和 BMP 家族蛋白之间的相互作用有许多记录。本研究的目的是使用 C2C12 细胞作为模型系统，揭示 FGF21 对 BMP-2 依赖性成骨活性的影响。我们发现 FGF21 增强了 C2C12 细胞系中 BMP-2 依赖性转录和成骨作用，碱性磷酸酶活性、基质矿化和基因表达证实了这一点。从机制上讲，FGF21 通过 Smad 蛋白增强 BMP-2 诱导的细胞内信号传导，但不通过 p44/42MAPK 蛋白增强。此外，我们还发现了一个负反馈环，其中 BMP-2 降低了内源性 FGF21 mRNA 的表达。总之，本研究证明BMP-2和FGF21通路之间存在体外相互作用，并且FGF21通过上调BMP-2依赖性Smad信号通路来增强BMP-2的成骨活性。 (C) 2013 Elsevier Inc. 保留所有权利。
Lifestyle-related diseases are increasing and the challenge to create innovative drugs to treat such diseases is a main focus in medical science research. Fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism, and is an innovative candidate drug already in clinical trials for type 2 diabetes mellitus and obesity. Bone fragility and impaired fracture healing induced by such lifestyle-related conditions are also a growing problem. Bone morphogenic proteins (BMPs) are well known osteogenic growth factors, and BMP-2 is used to augment bone formation in difficult clinical situations. There are many documented interactions between the FGF and BMP family proteins, although the interaction between FGF21 and BMP-2 remains unknown. The aim of this study was to reveal the effect of FGF21 toward BMP-2-dependent osteogenic activity, using C2C12 cells as a model system. We found that FGF21 enhanced BMP-2-dependent transcription and osteogenesis in the C2C12 cell line, which was confirmed by alkaline phosphatase activity, matrix mineralization, and gene expression. Mechanistically, FGF21 enhanced BMP-2-induced intracellular signaling through Smad proteins, but not through p44/ 42MAPK proteins. Furthermore, we identified a negative feedback loop in which BMP-2 decreased endogenous FGF21 mRNA expression. In summary, this study demonstrates interactions between BMP-2 and FGF21 pathways exist in vitro, and that FGF21 enhances the osteogenic activity of BMP-2 by up-regulating the BMP-2-dependent Smad signaling pathway. (C) 2013 Elsevier Inc. All rights reserved.