INTERLEUKIN-1 RECEPTOR ANTAGONIST AND TUMOR-NECROSIS-FACTOR BINDING-PROTEIN DECREASE OSTEOCLAST FORMATION AND BONE-RESORPTION IN OVARIECTOMIZED MICE

To investigate the contribution of IL-1, IL-6, and TNF to the increase d osteoclastogenesis induced by estrogen deficiency, ovariectomized (o vx) mice were treated with either IL-1 receptor antagonist (IL-1ra), a competitive inhibitor of IL-1, TNF binding protein (TNFbp), an inhibi tor of TNF, or the anti-IL-6 antibody (Ab) 20F3 for the first 2 wk aft er surgery. ovx increased the bone marrow cells secretion of IL-1 and TNF, but not IL-6, and the formation of TRAP-positive osteoclast-like multinucleated cells (MNCs) in bone marrow cultures treated with 1,25( OH)(2)D-3. The increase in MNC formation induced by ovx was prevented by in vivo treatment with either 17 beta estradiol, IL-1ra, TNFbp, or anti IL-6 Ab. However, the percent change in MNC formation induced by the anti-IL-6 Ab was similar in ovx and sham-operated animals, whereas IL-1ra and TNFbp were effective only in ovx mice. MNC formation was a lso decreased by in vitro treatment of bone marrow cultures with IL-1r a and TNFbp, but not with anti-IL-6 Ab. Ovx also increased bone resorp tion in vivo and in vitro, as assessed by the urinary excretion of pyr idinoline cross links and the formation of resorption pits, respective ly. IL-1ra, TNFbp and estrogen decreased bone resorption in vivo and i n vitro whereas the anti-IL-6 Ab inhibited bone resorption in vitro bu t not in vivo. In conclusion, these data indicate that IL-1 and TNF pl ay a direct role in mediating the effects of ovx on osteoclastogenesis and bone resorption. The data also suggest that IL-6 is not essential for increasing bone resorption in the early postovariectomy period.