title: Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells.
abstract: Mesenchymal stem cells (MSCs) are multipotent progenitors, which give rise to several lineages, including bone, cartilage and fat. Epidermal growth factor (EGF) stimulates cell growth, proliferation and differentiation. EGF acts by binding with high affinity to epidermal growth factor receptor (EGFR) on the cell surface and stimulating the intrinsic protein tyrosine kinase activity of its receptor, which initiates a signal transduction cascade causing a variety of biochemical changes within the cell and regulating cell proliferation and differentiation. We have identified BMP9 as one of the most osteogenic BMPs in MSCs. In this study, we investigate if EGF signalling cross-talks with BMP9 and regulates BMP9-induced osteogenic differentiation. We find that EGF potentiates BMP9-induced early and late osteogenic markers of MSCs in vitro, which can be effectively blunted by EGFR inhibitors Gefitinib and Erlotinib or receptor tyrosine kinase inhibitors AG-1478 and AG-494 in a dose- and time-dependent manner. Furthermore, EGF significantly augments BMP9-induced bone formation in the cultured mouse foetal limb explants. In vivo stem cell implantation experiment reveals that exogenous expression of EGF in MSCs can effectively potentiate BMP9-induced ectopic bone formation, yielding larger and more mature bone masses. Interestingly, we find that, while EGF can induce BMP9 expression in MSCs, EGFR expression is directly up-regulated by BMP9 through Smad1/5/8 signalling pathway. Thus, the cross-talk between EGF and BMP9 signalling pathways in MSCs may underline their important roles in regulating osteogenic differentiation. Harnessing the synergy between BMP9 and EGF should be beneficial for enhancing osteogenesis in regenerative medicine.
authors.affiliation: Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics designated by Chinese Ministry of Education and Chongqing Bureau of Education, Department of Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Qin
authors.forename: Qing
authors.initials: Q
authors.lastname: Luo
authors.forename: Yang
authors.initials: Y
authors.lastname: Bi
authors.forename: Gaohui
authors.initials: G
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Kim
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Su
authors.forename: Guoxin
authors.initials: G
authors.lastname: Nan
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: Yuhan
authors.initials: Y
authors.lastname: Kong
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Mary Rose
authors.initials: MR
authors.lastname: Rogers
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Shui
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Liang
authors.forename: Ningning
authors.initials: N
authors.lastname: Wu
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: He
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Shi
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Ming
authors.initials: M
authors.lastname: Li
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001857:Bone Matrix / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002828:Choristoma / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D055427:Growth Differentiation Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015415:Biomarkers; D055427:Growth Differentiation Factor 2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000469:Alkaline Phosphatase
keywords: BMP9 signalling; EGF signalling; mesenchymal stem cells; osteoblastic differentiation; osteogenic differentiation