PERSISTENT BONE-SPARING EFFECT OF INTERLEUKIN-1 RECEPTOR ANTAGONIST -A HYPOTHESIS ON THE ROLE OF IL-1 IN OVARIECTOMY-INDUCED BONE LOSS

The recent finding that treatment with the interleukin-l (IL-I) inhibi tor, interleukin-1 receptor antagonist (IL-1ra) decreases bone loss an d bone resorption in ovariectomized rats, strongly suggested that IL-1 mediates, at least in part, the effects of estrogen deficiency on bon e resorption. Although in vitro studies have shown that IL-1 activates mature osteoclasts and stimulates osteoclastogenesis, the two main me chanisms by which estrogen deficiency stimulates bone resorption, it i s still unclear whether IL-1 mediates both effects of estrogen deficie ncy in vivo. To investigate this matter, we have examined the changes in bone mineral density (BMD) which occur in ovariectomized rats after completion of 1 month of estrogen or IL-1ra treatment begun at the ti me of ovariectomy. Ovariectomy caused a marked decreased in BMD which was blocked by 17 beta estradiol and decreased by IL-1ra. Cessation of estrogen therapy was followed by a rapid induction of bone loss, indi cating that estrogen blocks the activation and utilization of mature o steoclasts without depleting the bone microenvironment of osteoclast p recursors and mature, inactive osteoclasts. In contrast, ovariectomize d rats treated with IL-1ra maintained a stable bone density for the fi rst 4 weeks after completion of the treatment. In these rats, bone los s resumed not earlier than 6 weeks after discontinuation of the IL-1ra treatment. Estrogen deficiency was necessary to unveil the bone-spari ng effect of IL-1ra because in a control experiment in which rats were treated with IL-1ra for the 4 weeks before ovariectomy, BMD began to decrease immediately after ovariectomy. Based on these results we prop ose the hypothesis that in conditions of estrogen deficiency, the main effect of IL-1ra is to block the proliferation and differentiation of osteoclast precursors, an event that results in the depletion of matu re, rapidly responsive osteoclasts. We also suggest that estrogen may have important direct effects on the regulation of osteoclast activity .