title: TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL.
abstract: TNFalpha is pivotal to the pathogenesis of inflammatory and possibly postmenopausal osteolysis. Much recent work has clarified mechanisms by which TNFalpha promotes osteoclastogenesis, but the means by which it activates osteoclasts to resorb bone remain uncertain. We found that very low concentrations of TNFalpha promoted actin ring formation, which correlates with functional activation in osteoclasts, both in osteoclasts formed in vitro and extracted from newborn rats. TNFalpha was equipotent with RANKL for this action. Activation by TNFalpha was unaffected by blockade of RANKL by OPG, its soluble decoy receptor, suggesting that this was due to a direct action on osteoclasts. Bone resorption was similarly directly and potently stimulated, in a RANKL-independent manner in osteoclasts, whether these were formed in vitro or in vivo. Interestingly, TNFalpha promoted actin ring formation at concentrations an order of magnitude below those required for osteoclastic differentiation. Moreover, TNFalpha strongly synergized with RANKL, such that miniscule concentrations of TNFalpha were sufficient to substantially augment osteoclast activation. The extreme sensitivity of osteoclasts to activation by TNFalpha suggests that the most sensitive osteolytic response of bone to TNFalpha is through activation of existing osteoclasts; and the strong synergy with RANKL provides a mechanism whereby increased osteolysis can be achieved without disturbance to the underlying pattern of osteoclastic localization.
authors.affiliation: Department of Cellular Pathology, St. George's Hospital Medical School, London SW17 ORE, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Fuller
authors.forename: Chiho
authors.initials: C
authors.lastname: Murphy
authors.forename: Barrie
authors.initials: B
authors.lastname: Kirstein
authors.forename: Simon W
authors.initials: SW
authors.lastname: Fox
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Chambers
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control; D002352:Carrier Proteins / Q000494:pharmacology*; D002469:Cell Separation; D004357:Drug Synergism; D007202:Indicators and Reagents; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D053245:RANK Ligand; D051381:Rats; D017208:Rats, Wistar; D053246:Receptor Activator of Nuclear Factor-kappa B; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D007202:Indicators and Reagents; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha