17 beta-estradiol antagonizes effects of 1 alpha,25-dihydroxyvitamin D-3 on interleukin-6 production and osteoclast-like cell formation in mouse bone marrow primary cultures

In mouse bone marrow primary cultures, the formation of osteoclast-like, i.e. tartrate-resistant acid phosphatase (TRAP)-and calcitonin receptor-positive multinucleated cells (MNC), when induced by 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), can be suppressed by 17 beta-estradiol (17 beta-E-2), whereas 17 alpha-E-2 is without any effect. 17 beta-E-2, above 10(-11) M, significantly reduced 1 alpha,25(OH)(2)D-3-mediated TRAP(+) MNC formation in cultured bone marrow cells from both female and male mice. The estrogen at 10(-8) M suppressed the peak response to the vitamin D sterol by 50%. 17 beta-E-2, significantly suppressed basal and 1 alpha,25(OH)(2)D-3-stimulated cellular production of interleukin (IL)-6. IL-6 alone, although bone marrow cells in hormone-free culture produced appreciable amounts of the cytokine, did not induce any TRAP(+) MNC. Therefore, the changes in IL-6 production induced by the hormones could not be the sole determinant for the extent of TRAP(+) MNC formation. However, the stimulatory effect of 1 alpha,25(OH)(2)D-3 on osteoclastogenesis nevertheless can be significantly reduced by a neutralizing monoclonal anti-IL-6 antibody. In the presence of 10(-8) M 17 beta-E-2, the anti-IL-6 monoclonal antibody does not achieve any further suppression of 1 alpha,25(OH)(2)D-3-related osteoclast-like cell formation. Our data suggest that induction of osteoclastogenesis by 1 alpha,25(OH)(2)D-3 is partially dependent on IL-6 signaling and can be modulated by 17 beta-E-2 through interference with IL-6 receptor activation, in addition to inhibition of IL-6 production by marrow stromal cells.