title: Timing, rather than the concentration of cyclic AMP, correlates to osteogenic differentiation of human mesenchymal stem cells.
abstract: Previously, we demonstrated that protein kinase A (PKA) activation using dibutyryl-cAMP in human mesenchymal stem cells (hMSCs) induces in vitro osteogenesis and bone formation in vivo. To further investigate the physiological role of PKA in hMSC osteogenesis, we tested a selection of G-protein-coupled receptor ligands which signal via intracellular cAMP production and PKA activation. Treatment of hMSCs with parathyroid hormone, parathyroid hormone-related peptide, melatonin, epinephrine, calcitonin or calcitonin gene-related peptide did not result in accumulation of cAMP or induction of alkaline phosphatase (ALP) expression. The only ligand that did induce cAMP, prostaglandin E2, even inhibited ALP expression and mineralization, suggesting that physiological levels of cAMP may inhibit osteogenesis. Furthermore, intermittent exposure of hMSCs to dibutyryl-cAMP inhibited ALP expression, whereas we did not observe an inhibitive effect at low dibutyryl-cAMP concentrations. Taken together, our results demonstrate that cAMP can either stimulate or inhibit osteogenesis in hMSCs, depending on the duration, rather than the strength, of the signal provided.
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.
authors.forename: Ramakrishnaiah
authors.initials: R
authors.lastname: Siddappa
authors.forename: Joyce
authors.initials: J
authors.lastname: Doorn
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Eli
authors.initials: E
authors.lastname: Langerwerf
authors.forename: Roel
authors.initials: R
authors.lastname: Arends
authors.forename: Clemens
authors.initials: C
authors.lastname: van Blitterswijk
authors.forename: Jan
authors.initials: J
authors.lastname: de Boer
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology; D013997:Time Factors
chemical_list: D008024:Ligands; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D000242:Cyclic AMP; D015232:Dinoprostone