title: Association of sustained ERK activity with integrin beta3 induction during receptor activator of nuclear factor kappaB ligand (RANKL)-directed osteoclast differentiation.
abstract: Osteoclast differentiation is a multi-step process that involves cell proliferation, commitment, and fusion. Some adhesion molecules, including integrin alphavbeta3, have been shown to have roles in osteoclast fusion. In the course of studying with pharmacologic agents known to inhibit protein tyrosine kinases of the Src family, we found that radicicol increased cell fusion during receptor activator of nuclear factor kappaB ligand (RANKL)-driven differentiation of osteoclasts at concentrations far below the ones shown to inhibit its targets in previous studies. Treatments of low doses of radicicol to RAW 264.7 cells that undergo osteoclastic differentiation in the presence of RANKL enhanced the RANKL-induced gene expression of integrin beta3 without any effect on the expression of integrin alphav, which was constitutively high. The cell surface level of integrin alphavbeta3 complexes was consequently augmented by radicicol. In addition, sustained ERK and MEK activation was observed in cells treated with both radicicol and RANKL. More importantly, modulation of ERK activity by the MEK inhibitor U0126 or the gene transduction of a constitutively active form of MEK resulted in a suppression and increment, respectively, of integrin beta3 induction by RANKL. Our data indicate that sustained ERK activity is associated with integrin beta3 induction and subsequent cell surface expression of the alphavbeta3 integrin complex, which may contribute to cell fusion during RANKL-directed osteoclastogenesis.
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002459:Cell Fusion; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D039661:Integrin beta3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D018942:Macrolides; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
chemical_list: D002070:Butadienes; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D007783:Lactones; D018942:Macrolides; D008562:Membrane Glycoproteins; D009570:Nitriles; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C035359:monorden