title: cAMP enhances BMP2-signaling through PKA and MKP1-dependent mechanisms.
abstract: Recent studies suggest that the elevation of intracellular cyclic adenosine monophosphate (cAMP) and the activation of the protein kinase A regulate BMP-induced osteogenesis. However, the precise mechanisms underlying the enhancing effect of cAMP on BMP2 signaling were not completely revealed. In this study we investigated the effect of elevated cAMP level and PKA activation on the BMP2-induced osteoblastic differentiation in pluripotent C2C12 cells. Alkaline phosphatase activity and its mRNA were consistently induced by BMP2 treatment. The pretreatment of C2C12 cells with Forskolin, a cAMP generating agent, dbcAMP, an analogue of cAMP, or IBMX (3-isobutyl 1-methyl xanthine), and a nonspecific inhibitor of phosphodiesterases elicited further activation of alkaline phosphatase. Furthermore, elevated intracellular cAMP level increased BMP2-induced MKP1. On the other hand, BMP2-induced Erk phosphorylation (p44/p42) and cell proliferation were suppressed in the presence of cAMP. Thus, cAMP might enhance BMP2-induced osteoblastic differentiation by a MKP1-Erk-dependent mechanism.
authors.affiliation: Oral Biotechnology & Bioengineering, Dept. of Cranio-Maxillofacial Surgery, University Hospital, Zürich, Switzerland.
authors.forename: Chafik
authors.initials: C
authors.lastname: Ghayor
authors.forename: Martin
authors.initials: M
authors.lastname: Ehrbar
authors.forename: Blanca
authors.initials: B
authors.lastname: San Miguel
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Grätz
authors.forename: Franz E
authors.initials: FE
authors.lastname: Weber
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D054338:Cell Transdifferentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D015675:Osteocalcin / Q000096:biosynthesis; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000469:Alkaline Phosphatase; D054638:Dual Specificity Phosphatase 1