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-lik e, i.e. tartrate-resistant acid phosphatase (TRAP)-and calcitonin rece ptor-positive multinucleated cells (MNC), when induced by 1 alpha,25-d ihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3), can be suppressed by 17 be ta-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 pe ak 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 product ion of interleukin (IL)-6. IL-6 alone, although bone marrow cells in h ormone-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 exte nt of TRAP(+) MNC formation. However, the stimulatory effect of 1 alph a,25(OH)(2)D-3 on osteoclastogenesis nevertheless can be significantly reduced by a neutralizing monoclonal anti-IL-6 antibody. In the prese nce of 10(-8) M 17 beta-E-2, the anti-IL-6 monoclonal antibody does no t achieve any further suppression of 1 alpha,25(OH)(2)D-3-related oste oclast-like cell formation. Our data suggest that induction of osteocl astogenesis by 1 alpha,25(OH)(2)D-3 is partially dependent on IL-6 sig naling and can be modulated by 17 beta-E-2 through interference with I L-6 receptor activation, in addition to inhibition of IL-6 production by marrow stromal cells.