INCREASED INTERLEUKIN-6 PRODUCTION BY MURINE BONE-MARROW AND BONE-CELLS AFTER ESTROGEN WITHDRAWAL

We have previously shown that cytokine-induced production of interleuk in-6 (IL-6) by cultured bone marrow-derived stromal and osteoblastic c ells is inhibited by 17beta-estradiol, and that estrogen withdrawal ( ovariectomy) in mice causes an up-regulation of osteoclast development which can be prevented by a neutralizing antibody against IL-6 or est rogen replacement. To directly establish the link between estrogen los s and altered IL-6 production, implied by our earlier studies, we have now compared IL-6 production in ex vivo cultures of bone marrow cells from mice that were sham operated, ovariectomized, or ovariectomized and treated with 17beta-estradiol. In addition, we have examined the e ffect of the in vitro withdrawal of estrogens from primary cell cultur es of neonatal murine calvaria on IL-6 production. IL-6 production in ex vivo cultures of bone marrow cells maintained in the presence of 1, 25-dihydroxyvitamin D3 or PTH was greater in marrow cells from ovariec tomized mice than in those from sham-operated animals or ovariectomize d animals receiving estrogen replacement. In line with this finding, a ddition of 17beta-estradiol to calvaria cell cultures followed by with drawal of the steroid caused an increase in the amount of IL-6 produce d in response to the subsequent stimulation of these cultures with IL- 1 or PTH compared to that in cultures that had never been treated with estradiol; when the inactive isomer 17alpha-estradiol was used, no ch ange in IL-6 production was observed. These results establish that est rogen loss causes an up-regulation of IL-6 production by bone marrow c ells and that a similar phenomenon can be elicited in vitro by withdra wal of 17beta-estradiol from primary cultures of bone cells.