title: A novel collagen-binding peptide promotes osteogenic differentiation via Ca2+/calmodulin-dependent protein kinase II/ERK/AP-1 signaling pathway in human bone marrow-derived mesenchymal stem cells.
abstract: The intracellular signaling events controlling human mesenchymal stem cell (hMSC) differentiation into osteoblasts are poorly understood. Collagen-binding domain is considered an essential component of bone mineralization. In the present study, we investigated the regulatory mechanism of osteoblastic differentiation of hMSC by the peptide with a novel collagen-binding motif derived from osteopontin. The peptide induced influx of extracellular Ca2+ via calcium channels and increased intracellular Ca2+ concentration ([Ca2+]i) independent of both pertussis toxin and phospholipase C, and activated ERK, which was inhibited by Ca2+/calmodulin-dependent protein kinase (CaMKII) antagonist, KN93. The peptide-induced increase of [Ca2+]i is correlated with ERK activation in a various cell types. The peptide stimulated the migration of hMSC but suppressed cell proliferation. Furthermore, the peptide increased the phosphorylation of cAMP-response element-binding protein, leading to a significant increase in the transactivation of cAMP-response element and serum response element. Ultimately, the peptide increased AP-1 transactivation, c-jun expression, and bone mineralization, which are suppressed by KN93. Taken together, these results indicate that the novel collagen-binding peptide promotes osteogenic differentiation via Ca2+/CaMKII/ERK/AP-1 signaling pathway in hMSC, suggesting the potential application in cell therapy for bone regeneration.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735, Republic of Korea.
authors.forename: Min Kyoung
authors.initials: MK
authors.lastname: Shin
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.forename: Seung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Chong-Pyoung
authors.initials: CP
authors.lastname: Chung
authors.forename: Yoon-Jeong
authors.initials: YJ
authors.lastname: Park
authors.forename: Do Sik
authors.initials: do S
authors.lastname: Min
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D053495:Osteopontin / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C115163:CREB1 protein, human; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D053495:Osteopontin; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases