ENDOGENOUS BONE-RESORBING FACTORS IN ESTROGEN DEFICIENCY - COOPERATIVE EFFECTS OF IL-1 AND IL-6

Estrogen deficiency causes a marked bone loss by stimulating osteoclas tic bone resorption, To explore the endogenous bone-resorbing factors involved in estrogen deficiency, we examined the bone-resorbing activi ty present in the supernatant fraction of mouse bone marrow collected from ovariectomized (OVX) mice, Adding bone marrow supernatants at 20- 80% to organ cultures of mouse long bones dose-dependently stimulated bone resorption, The endogenous bone-resorbing activity present in bon e marrow supernatants from OVX mice was much higher than that from sha m-operated mice 2-4 weeks after surgery, and it was significantly dimi nished by indomethacin in vitro, Anti-IL-1 alpha antibody completely n eutralized the bone-resorbing activity present in bone marrow supernat ants from OVX mice, Antibodies against IL-1 beta, IL-6, and IL-6 recep tors also neutralized it, but partially, The concentration of IL-1 alp ha measured by ELISA was much higher in bone marrow supernatants than in sera, but it was not appreciably changed before or after OVX, The c oncentration of IL-1 beta in bone marrow supernatants from OVX mice wa s less than the detection limit. OVX stimulated IL-1 activity in bone marrow supernatants measured by means of the proliferation of thymocyt es, However, the level of IL-1 alpha present in bone marrow supernatan ts from OVX mice was insufficient to stimulate bone resorption, Compar ed with the serum concentration, bone marrow supernatants contained a much higher level of IL-6 as well, and it was further increased by OVX , However, IL-6 alone present in bone marrow supernatants from OVX mic e again did not stimulate bone resorption, The concurrent addition of IL-1 (50 pg/ml), IL-6 (0.2 ng/ml), sIL-6 receptor (1 ng/ml), and PGE(2 ) (7 ng/ml), which equaled the endogenous concentrations in bone marro w supernatants from OVX mice, co-operatively induced bone resorption, These results suggest that the enhanced bone resorption that occurs du ring estrogen deficiency is due to multi-factors rather than to a sing le factor.