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Receptor Activator of NF-B Ligand Inhibition Suppresses Bone Resorption and Hypercalcemia but Does Not Affect Host Immune Responses to Influenza Infection¹

Robert E. Miller^*, Daniel Branstetter, Allison Armstrong^*, Bryan Kennedy^*, Jon Jones^*, Laine Cowan, Jeanine Bussiere and William C. Dougall^2,*

^* Department of Cancer Biology, Department of Pathology, and Toxicology, Amgen Washington, Seattle, WA 98119; and Department of Toxicology, Amgen, Thousand Oaks, CA 91320

Receptor activator of NF-B (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 D₃ (1,25(OH)₂D₃)-induced hypercalcemia. Mice were injected with a single dose of 0, 10, 100, 500, or 1000 µg of RANK-Fc; 100 µg of OPG-Fc; or 5 µg of zoledronate 2 h before 1,25(OH)₂D₃ challenge on day 0, and sacrificed on days 1, 2, 4, 6, 8, 12, 16, and 20. RANK-Fc doses of 100 or 500 µg were tested in a mouse respiratory influenza virus host-resistance model. A single dose of RANK-Fc 100 µg 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 0.01 vs controls). By day 6, both immature and mature osteoclasts were depleted by high doses of RANK-Fc (500 and 1000 µg) or 100 µg of OPG-Fc. RANK-Fc doses of 100 or 500 µg 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Amgen.

² Address correspondence and reprint requests to Dr. William C. Dougall, Amgen Washington, 1201 Amgen Court West, Seattle, WA 98119-3105. E-mail address: dougallw{at}amgen.com

³ Abbreviations used in this paper: RANK, receptor activator of NF-B; BMD, bone mineral density; E-MEM, Eagle’s MEM; HHM, humoral hypercalcemia of malignancies; OPG, osteoprotegerin; PYD, pyridinoline; RANKL, RANK ligand; TRAP, tartrate-resistant acid phosphatase.

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