title: BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells.
abstract: Mesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1α (HIF1α)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces HIF1α expression in MSCs through Smad1/5/8 signaling. Exogenous expression of HIF1α potentiates BMP9-induced osteogenic differentiation of MSCs both in vitro and in vivo. siRNA-mediated silencing of HIF1α or HIF1α inhibitor CAY10585 profoundly blunts BMP9-induced osteogenic signaling in MSCs. HIF1α expression regulated by cobalt-induced hypoxia also recapitulates the synergistic effect between HIF1α and BMP9 in osteogenic differentiation. Mechanistically, HIF1α is shown to exert its synergistic effect with BMP9 by inducing both angiogenic signaling and osteogenic signaling in MSCs. Thus, our findings should not only expand our understanding of the molecular basis behind BMP9-regulated osteoblastic lineage-specific differentiation, but also provide an opportunity to harness the BMP9-induced synergy between osteogenic and angiogenic signaling pathways in regenerative medicine.
authors.affiliation: The First Affiliated Hospital and the Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Hu
authors.forename: Dianming
authors.initials: D
authors.lastname: Jiang
authors.forename: Enyi
authors.initials: E
authors.lastname: Huang
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Ruidong
authors.initials: R
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Liang
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Kim
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Jian-Li
authors.initials: JL
authors.lastname: Gao
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
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: Wei
authors.initials: W
authors.lastname: Shui
authors.forename: Xiaoji
authors.initials: X
authors.lastname: Luo
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Mary Rose
authors.initials: MR
authors.lastname: Rogers
authors.forename: Jikun
authors.initials: J
authors.lastname: Shen
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Ningning
authors.initials: N
authors.lastname: Wu
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D055412:Growth Differentiation Factors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000502:physiology; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051793:Hypoxia-Inducible Factor 1