Crosstalk between tyrosine kinase receptors,GSK3 and BMP2 signaling during osteoblastic differentiation of human mesenchymal stem cells |
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Authors: | Emmanuel Biver Cyril Thouverey David Magne Joseph Caverzasio |
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Institution: | 1. Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland;2. Pathophysiology of Inflammatory Bone Diseases, PMOI EA4490, Boulogne/Mer, France;3. Institut of Molecular and Supramolecular Biochemistry, UMR, CNRS 5246, University of Lyon 1, 69622 Villeurbanne Cedex, France |
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Abstract: | Bone morphogenic proteins (BMPs) promote mesenchymal stem cell (MSC) osteogenic differentiation, whereas platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) activate their proliferation through receptors tyrosine kinase (RTK). The effects of PDGF or FGF receptor signaling pathway on BMP2-induced osteoblastic differentiation was investigated in human MSC (HMSC). Inhibition of PDGF or/and FGF receptors enhanced BMP2-induced alkaline phosphatase (ALP) activity, expression of Osterix, ALP and Bone sialoprotein, and matrix calcification. These effects were associated with increased Smad-1 activity, indicating that mitogenic factors interfere with Smad signaling in HMSC differentiation. RTK activate MAPK and inhibit GSK3 through the PI3K/Akt pathway. Biochemical analysis indicated that MAPK JNK and GSK3 especially are potential signaling molecules regulating BMP-induced osteoblastic HMSC differentiation. These observations highlight that the osteogenic effects of BMP2 are modulated by mitogenic factors acting through RTK. |
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Keywords: | BMPs bone morphogenic proteins TGF-β transforming growth factor beta MSC mesenchymal stem cell PDGF platelet derived growth factor FGF fibroblast growth factor EGF epidermal growth factor RTK receptors tyrosine kinase HMSC human MSC ALP alkaline phosphatase MAPK Mitogen-Activated-Protein Kinase ERK extracellular signal regulated kinases JNK c-Jun amino-terminal kinases GSK3 glycogen synthase kinase 3 OSX osterix BSP bone sialoprotein |
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