Regulatory actions of 3',5'-cyclic adenosine monophosphate on osteoclast function: possible roles of Epac-mediated signaling.
Annals of the New York Academy of Sciences
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Jeevaratnam, K., Salvage, S., Li, M., & Huang, C. (2018). Regulatory actions of 3',5'-cyclic adenosine monophosphate on osteoclast function: possible roles of Epac-mediated signaling.. Annals of the New York Academy of Sciences, 1433 (1), 18-28. https://doi.org/10.1111/nyas.13861
Alterations in cellular levels of the second messenger 3'-5'-cyclic adenosine monophosphate [cAMP]i regulate a wide range of physiologically important cellular signalling processes in numerous cell types. Osteoclasts are terminally differentiated, multinucleated cells specialised for bone resorption. Their systemic regulator, calcitonin, triggers morphometrically and pharmacologically distinct, retraction (‘R’) and quiescence (‘Q’), effects respectively on cell-spread area and protrusion-retraction motility paralleling its inhibition of bone resorption. Q effects were reproduced by cholera toxin-mediated Gs-protein activation known to increase [cAMP]i, unaccompanied by the [Ca2+]i changes contrastingly associated with R effects. We explore a hypothesis implicating cAMP-signalling involving guanine nucleotide-exchange activation of the small GTPase Ras-proximate-1 (Rap1) by exchange proteins directly activated by cAMP (Epac). Rap1 activates integrin clustering, cell adhesion to bone matrix, associated cytoskeletal modifications and signalling processes, and transmembrane transduction functions. Epac activation enhanced, whereas Epac inhibition or shRNA-mediated knockdown compromised the appearance of markers for osteoclast differentiation and motility following receptor activator of nuclear factor kappa-Β ligand (RANKL) stimulation. Deficiencies in talin and Rap1 compromised in vivo bone resorption producing osteopetrotic phenotypes in genetically modified murine models. Translational implications for an Epac-Rap1 signalling hypothesis in relationship to N-bisphosphonate actions on prenylation and membrane localisation of small GTPases are discussed.
Osteoclasts, Animals, Humans, Osteoporosis, Bone Resorption, Diphosphonates, Calcitonin, rap1 GTP-Binding Proteins, Cyclic AMP-Dependent Protein Kinases, Guanine Nucleotide Exchange Factors, Integrins, Cyclic AMP, Signal Transduction, Cell Movement, Second Messenger Systems, Calcium Signaling, Models, Biological, Bone Density Conservation Agents, Translational Medical Research
Medical Research Council
British Heart Foundation (PG/14/79/31102)
External DOI: https://doi.org/10.1111/nyas.13861
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278847