Timing, rather than the concentration of cyclic AMP, correlates to osteogenic differentiation of human mesenchymal stem cells

R. Siddappa, J. Doorn, J. Liu, Eli Langerwerf, Roel Arends, Clemens van Blitterswijk, Jan de Boer

Research output: Contribution to journalArticleAcademic

27 Citations (Scopus)


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.
Original languageUndefined
Pages (from-to)356-365
JournalJournal of tissue engineering and regenerative medicine
Issue number5
Publication statusPublished - 2010


  • parathyroid hormone
  • IR-72586
  • osteogenic differentiation
  • GPCR ligands
  • Human mesenchymal stem cells
  • prostaglandin E2
  • protein kinase A

Cite this