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.