Receptor activator of NF-kappa B ligand inhibition suppresses bone resorption and hypercalcemia but does not affect host immune responses to influenza infection.
Receptor activator of NF-kappaB (RANK) and its ligand (RANKL) are essential for osteoclast formation, function, and survival. Osteoprotegerin (OPG) inhibits RANK signaling by sequestering RANKL. This study evaluated the antiosteoclast and immunoregulatory effects of mouse rRANK-Fc, which, similar to OPG, can bind RANKL. The effect of RANKL inhibition by RANK-Fc on osteoclast function was determined by inhibition of vitamin D(3) (1,25(OH)(2)D(3))-induced hypercalcemia. Mice were injected with a single dose of 0, 10, 100, 500, or 1000 microg of RANK-Fc; 100 microg of OPG-Fc; or 5 microg of zoledronate 2 h before 1,25(OH)(2)D(3) challenge on day 0, and sacrificed on days 1, 2, 4, 6, 8, 12, 16, and 20. RANK-Fc doses of 100 or 500 microg were tested in a mouse respiratory influenza virus host-resistance model. A single dose of RANK-Fc > or =100 microg suppressed elevation of serum calcium levels and suppressed the bone turnover marker serum pyridinoline at day 4 and later time points, similar to those observed with OPG-Fc and zoledronate (p < or = 0.01 vs controls). By day 6, both immature and mature osteoclasts were depleted by high doses of RANK-Fc (500 and 1000 microg) or 100 microg of OPG-Fc. RANK-Fc doses of 100 or 500 microg had no detectable effect on immune responses to influenza infection, as measured by activation of cytotoxic T cell activity, influenza-specific IgG response, and virus clearance. RANK-Fc inhibition of RANKL has antiosteoclast activity at doses that have no detectable immunoregulatory activity, suggesting that RANKL inhibitors be further studied for their potential to treat excess bone loss.
Miller
Robert E
RE
Department of Cancer Biology, Amgen Washington, 1201 Amgen Court West, Seattle, WA 98119, USA.
Branstetter
Daniel
D
Armstrong
Allison
A
Kennedy
Bryan
B
Jones
Jon
J
Cowan
Laine
L
Bussiere
Jeanine
J
Dougall
William C
WC
D000818:Animals; D001862:Bone Resorption / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D004164:Diphosphonates / Q000008:administration & dosage; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006887:Hydroxycholecalciferols / Q000633:toxicity; D006934:Hypercalcemia / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000008:administration & dosage; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D053244:Osteoprotegerin / Q000008:administration & dosage / Q000276:immunology; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D000077211:Zoledronic Acid
D004164:Diphosphonates; D006887:Hydroxycholecalciferols; D007093:Imidazoles; D007074:Immunoglobulin G; D053244:Osteoprotegerin; D053245:RANK Ligand; C517736:Rank-Fc; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins; C506031:Tnfrsf11b protein, mouse; D000077211:Zoledronic Acid; C030049:1,25,26-trihydroxyvitamin D3