Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells
Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells
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生长激素通过激活小鼠多系细胞中的 JAK/STAT/IGF1 通路与 BMP9 协同促进成骨分化
DOI：
10.1002/jbmr.1622
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发表时间：
2012-07-01
影响因子：
6.2
通讯作者：
He, Tong-Chuan
中科院分区：
文献类型：
--
作者：
Huang, Enyi;Zhu, Gaohui;He, Tong-Chuan
生长激素（growth hormone，GH）是垂体前叶生长激素细胞对GH释放激素的应答而释放的激素，在骨骼发育和出生后生长发育中起重要作用。然而，目前尚不清楚垂体外GH是否对小鼠多系细胞（MMCs）产生任何影响。MMCs是多能祖细胞，产生几种谱系，包括骨、软骨和脂肪。我们已经确定骨形态发生蛋白9（BMP 9）作为一个最成骨的BMPs在MMCs通过调节一组独特的下游介质。在本研究中，我们通过表达谱分析发现GH是BMP 9在小鼠MMCs中最显著上调的基因之一。我们证实，生长激素是一个直接的早期目标和上调BMP 9信号。外源性GH与BMP 9协同诱导MMC中的早期和晚期成骨标志物。此外，BMP 9和GH共刺激导致在培养的肢体外植体中生长板的显著扩增。虽然单独GH在异位骨形成模型中不诱导从头骨形成，但BMP 9和GH共刺激的MMC形成更成熟的骨，这可以通过沉默GH表达来抑制。JAK/STAT抑制剂可显著减弱BMP 9和GH之间的协同成骨活性，导致MMC中GH调节的胰岛素样生长因子1（IGF 1）表达减少。我们的研究结果强烈表明，BMP 9可以有效地调节垂体外生长激素在MMC的表达。因此，可以想象，BMP 9-GH-IGF轴可以被利用作为一种创新策略，以增强再生医学中的骨生成。(c)2012年美国骨与矿物质研究学会。
Growth hormone (GH) is usually released by somatotrophs in the anterior pituitary in response to the GH-releasing hormone and plays an important role in skeleton development and postnatal growth. However, it is unclear if extrapituitary GH exerts any effect on murine multilineage cells (MMCs). MMCs are multipotent progenitors that give rise to several lineages, including bone, cartilage, and fat. We have identified bone morphogenic protein 9 (BMP9) as one of the most osteogenic BMPs in MMCs by regulating a distinct set of downstream mediators. In this study, we find that GH is one of the most significantly upregulated genes by BMP9 in mouse MMCs through expression-profiling analysis. We confirm that GH is a direct early target of and upregulated by BMP9 signaling. Exogenous GH synergizes with BMP9 on inducing early and late osteogenic markers in MMCs. Furthermore, BMP9 and GH costimulation leads to a significant expansion of growth plate in cultured limb explants. Although GH alone does not induce de novo bone formation in an ectopic bone formation model, BMP9 and GH costimulated MMCs form more mature bone, which can be inhibited by silencing GH expression. The synergistic osteogenic activity between BMP9 and GH can be significantly blunted by JAK/STAT inhibitors, leading to a decrease in GH-regulated insulin-like growth factor 1 (IGF1) expression in MMCs. Our results strongly suggest that BMP9 may effectively regulate extrapituitary GH expression in MMCs. Thus, it is conceivable that the BMP9-GH-IGF axis may be exploited as an innovative strategy to enhance osteogenesis in regenerative medicine. (c) 2012 American Society for Bone and Mineral Research.