Cross‐talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells

• Published in: Journal of cellular and molecular medicine Vol. 17; no. 9; pp. 1160 - 1172
• Main Authors: Liu, Xing, Qin, Jiaqiang, Luo, Qing, Bi, Yang, Zhu, Gaohui, Jiang, Wei, Kim, Stephanie H., Li, Mi, Su, Yuxi, Nan, Guoxin, Cui, Jing, Zhang, Wenwen, Li, Ruidong, Chen, Xiang, Kong, Yuhan, Zhang, Jiye, Wang, Jinhua, Rogers, Mary Rose, Zhang, Hongyu, Shui, Wei, Zhao, Chen, Wang, Ning, Liang, Xi, Wu, Ningning, He, Yunfeng, Luu, Hue H., Haydon, Rex C., Shi, Lewis L., Li, Tingyu, He, Tong‐Chuan, Li, Ming
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-09-2013
• Subjects: Alkaline Phosphatase - metabolism; Animals; Biomarkers - metabolism; BMP9 signalling; Bone Matrix - drug effects; Calcification, Physiologic - drug effects; Cell Differentiation - drug effects; Choristoma - pathology; EGF signalling; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; Extremities - embryology; Fetus - drug effects; Fetus - metabolism; Growth Differentiation Factor 2 - metabolism; Growth Differentiation Factor 2 - pharmacology; Humans; mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - enzymology; Mice; Original; osteoblastic differentiation; Osteogenesis - drug effects; osteogenic differentiation; Receptor Cross-Talk - drug effects; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects; EGF signalling; osteoblastic differentiation; mesenchymal stem cells; osteogenic differentiation; BMP9 signalling
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.12097

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.