Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells

作者：Enyi Huang, Gaohui Zhu, Wei Jiang, Ke Yang, Yanhong Gao, Qing Luo, Jian‐Li Gao, Stephanie H. Kim, Xing Liu, Mi Li, Qiong Shi, Ning Hu, Linyuan Wang, Hong Liu, Jing Cui, Wenwen Zhang, Ruidong Li, Xiang Chen, Yuhan Kong, Jiye Zhang, Jinhua Wang, Jikun Shen, Yang Bi, Joseph M. Statz, Bai‐Cheng He, Jinyong Luo, Huicong Wang, Feng Xiong, Hue H. Luu, Rex C. Haydon, Li Yang, Tong‐Chuan He · 发表于：Journal of Bone and Mineral Research · 年份：2012 · DOI：10.1002/jbmr.1622 · 被引用次数：119 · 研究领域：TGF-β signaling in diseases、Growth Hormone and Insulin-like Growth Factors、Genetic Syndromes and Imprinting

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 conceiv...