Regulatory actions of 3′,5′-cyclic adenosine monophosphate on osteoclast function: possible roles of Epac-mediated signaling

Autor:	Kamalan Jeevaratnam, Mengye Li, Christopher L.-H. Huang, Samantha C. Salvage
Rok vydání:	2018
Předmět:	0301 basic medicine Cell signaling biology Chemistry General Neuroscience General Biochemistry Genetics and Molecular Biology Bone resorption Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure History and Philosophy of Science RANKL Osteoclast Second messenger system biology.protein medicine Small GTPase Cyclic adenosine monophosphate Rap1 030217 neurology & neurosurgery
Zdroj:	Annals of the New York Academy of Sciences. 1433:18-28
ISSN:	0077-8923
DOI:	10.1111/nyas.13861
Popis:	Alterations in cellular levels of the second messenger 3',5'-cyclic adenosine monophosphate ([cAMP]i ) regulate a wide range of physiologically important cellular signaling processes in numerous cell types. Osteoclasts are terminally differentiated, multinucleated cells specialized for bone resorption. Their systemic regulator, calcitonin, triggers morphometrically and pharmacologically distinct retraction (R) and quiescence (Q) effects on cell-spread area and protrusion-retraction motility, respectively, 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 signaling 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 signaling 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 stimulation by receptor activator of nuclear factor kappa-Β ligand (RANKL). Deficiencies in talin and Rap1 compromised in vivo bone resorption, producing osteopetrotic phenotypes in genetically modified murine models. Translational implications of an Epac-Rap1 signaling hypothesis in relationship to N-bisphosphonate actions on prenylation and membrane localization of small GTPases are discussed.
Databáze:	OpenAIRE
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