title: Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells.
abstract: 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.
authors.affiliation: School of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Enyi
authors.initials: E
authors.lastname: Huang
authors.forename: Gaohui
authors.initials: G
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gao
authors.forename: Qing
authors.initials: Q
authors.lastname: Luo
authors.forename: Jian-Li
authors.initials: JL
authors.lastname: Gao
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Kim
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.forename: Ning
authors.initials: N
authors.lastname: Hu
authors.forename: Linyuan
authors.initials: L
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.forename: Ruidong
authors.initials: R
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Kong
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Jikun
authors.initials: J
authors.lastname: Shen
authors.forename: Yang
authors.initials: Y
authors.lastname: Bi
authors.forename: Joseph
authors.initials: J
authors.lastname: Statz
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
authors.forename: Jinyong
authors.initials: J
authors.lastname: Luo
authors.forename: Huicong
authors.initials: H
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Xiong
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
mesh_terms: D000818:Animals; D019070:Cell Lineage; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D055427:Growth Differentiation Factor 2 / Q000378:metabolism*; D055412:Growth Differentiation Factors / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D010012:Osteogenesis; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D050791:STAT Transcription Factors; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D053613:Janus Kinase 1