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Endocrinology Vol. 143, No. 3 1108-1118
Copyright © 2002 by The Endocrine Society

PTH-CALCITONIN-VITAMIN D-BONE

TNF{alpha} Potently Activates Osteoclasts, through a Direct Action Independent of and Strongly Synergistic with RANKL

Karen Fuller, Chiho Murphy, Barrie Kirstein, Simon W. Fox and Timothy J. Chambers

Department of Cellular Pathology, St. George’s Hospital Medical School, London SW17 ORE, United Kingdom

Address all correspondence and requests for reprints to: T. J. Chambers, Department of Cellular Pathology, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail: . t.chambers{at}sghms.ac.uk

TNF{alpha} is pivotal to the pathogenesis of inflammatory and possibly postmenopausal osteolysis. Much recent work has clarified mechanisms by which TNF{alpha} promotes osteoclastogenesis, but the means by which it activates osteoclasts to resorb bone remain uncertain. We found that very low concentrations of TNF{alpha} promoted actin ring formation, which correlates with functional activation in osteoclasts, both in osteoclasts formed in vitro and extracted from newborn rats. TNF{alpha} was equipotent with RANKL for this action. Activation by TNF{alpha} 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, TNF{alpha} promoted actin ring formation at concentrations an order of magnitude below those required for osteoclastic differentiation. Moreover, TNF{alpha} strongly synergized with RANKL, such that miniscule concentrations of TNF{alpha} were sufficient to substantially augment osteoclast activation. The extreme sensitivity of osteoclasts to activation by TNF{alpha} suggests that the most sensitive osteolytic response of bone to TNF{alpha} 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.




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