title: Hepatocyte growth factor and p38 promote osteogenic differentiation of human mesenchymal stem cells.
abstract: Hepatocyte growth factor (HGF) is a paracrine factor involved in organogenesis, tissue repair, and wound healing. We report here that HGF promotes osteogenic differentiation through the transcription of key osteogenic markers, including osteocalcin, osterix, and osteoprotegerin in human mesenchymal stem cells and is a necessary component for the establishment of osteoblast mineralization. Blocking endogenous HGF using PHA665752, a c-Met inhibitor (the HGF receptor), or an HGF-neutralizing antibody attenuates mineralization, and PHA665752 markedly reduced alkaline phosphatase activity. Moreover, we report that HGF promotion of osteogenic differentiation involves the rapid phosphorylation of p38 and differential regulation of its isoforms, p38α and p38β. Western blot analysis revealed a significantly increased level of p38α and p38β protein, and reverse transcription quantitative PCR revealed that HGF increased the transcriptional level of both p38α and p38β. Using small interfering RNA to reduce the transcription of p38α and p38β, we saw differential roles for p38α and p38β on the HGF-induced expression of key osteogenic markers. In summary, our data demonstrate the importance of p38 signaling in HGF regulation of osteogenic differentiation.
authors.affiliation: Geriatric Research, Education, and Clinical Center and Research Service (K.K.A., K.M.C., B.A.R., G.A.H.), Veterans Affairs Medical Center, Miami, Florida 33125; Departments of Medicine (B.A.R., G.A.H.), Neurology (B.A.R.), and Biochemistry & Molecular Biology (K.M.C., G.A.H.), University of Miami Miller School of Medicine, Miami, Florida 33101.
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Aenlle
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Curtis
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Roos
authors.forename: Guy A
authors.initials: GA
authors.lastname: Howard
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D010012:Osteogenesis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14