Crosstalk between tyrosine kinase receptors, GSK3 and BMP2 signaling during osteoblastic differentiation of human mesenchymal stem cells.
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.
Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland; Pathophysiology of Inflammatory Bone Diseases, PMOI EA4490, Boulogne/Mer, France.
Emmanuel
E
Biver
Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland.
Cyril
C
Thouverey
Institut of Molecular and Supramolecular Biochemistry, UMR, CNRS 5246, University of Lyon 1, 69622 Villeurbanne Cedex, France.
David
D
Magne
Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland. Electronic address: Joseph.Caverzasio@unige.ch.
Joseph
J
Caverzasio
D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D055815:Young Adult
D055396:Bone Morphogenetic Protein 2; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D051785:Smad Proteins; D005346:Fibroblast Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
ALP; BMPs; BSP; Bone morphogenic proteins; EGF; ERK; FGF; Fibroblast growth factor; GSK3; HMSC; JNK; MAPK; MSC; Mesenchymal stem cells; Mitogen-Activated-Protein Kinase; OSX; Osteoblastic differentiation; PDGF; Platelet derived growth factor; RTK; TGF-β; Wnt/ß-catenin; alkaline phosphatase; bone morphogenic proteins; bone sialoprotein; c-Jun amino-terminal kinases; epidermal growth factor; extracellular signal regulated kinases; fibroblast growth factor; glycogen synthase kinase 3; human MSC; mesenchymal stem cell; osterix; platelet derived growth factor; receptors tyrosine kinase; transforming growth factor beta