Alendronate/interleukin-1β cotreatment increases interleukin-6 in bone and UMR-106 cells:: Dose dependence and relationship to the antiresorptive effect of alendronate

Aminobisphosphonates inhibit bone resorption but have been shown to elicit acute-phase-like elevations in interleukin-6 (IL-6) in bone in vitro. The current studies were carried out to determine the relationship between the antiresorptive effects of the aminobisphosphonate alendronate and its effects on IL-6, Resorption was elicited in cultured 19-day fetal rat Limb bones by 72 h treatment with interleukin-1 beta (IL-1 beta). Bone mass,vas quantitated at the end of the culture period to assess resorption, IL-6 was determined by bioassay (7TDI cell proliferation). IL-1 beta (18 and 180 pM) stimulated bone resorption and increased IL-6, Alendronate (70 mu M) inhibited the IL-1 beta-stimulated resorption. Alendronate alone did not affect IL-6 production by the bones, The IL-6 production from bones stimulated with 18 pM IL-1 beta was not significantly affected by alendronate, but the IL-6 production from bones stimulated with 180 pM IL-1 beta plus alendronate (21 and 70 mu M) was higher than with IL-1 beta alone, Indomethacin (1 mM) inhibited the IL-6 increase elicited by 180 pM IL-1 beta and the enhanced IL-6 production elicited by cotreatment with IL-1 beta and alendronate, Since bone cultures contain multiple cell types, further experiments were carried out to determine whether alendronate could increase IL-1 beta-stimulated IL-6 production in an osteoblast cell line, UMR-106. Alendronate alone did not affect IL6 in UMR-106 cells. Alendronate (70 mu M) in combination with IL-1 beta (180, 1.8, or 8 nM), or 7 mu M alendronate, in combination with 8 nhl IL-1 beta, significantly increased IL-6 in 48 h cell cultures, The results from the bone organ cultures show that alendronate can enhance IL-6 production elicited hy higher concentrations of the cytokine IL-1 beta in bone, but that this effect on IL-6 does not prevent the inhibitory actions of alendronate on bone resorption, The results with the UMR106 cells indicate that one cellular site at which this enhancement of IL-6 production can occur is the osteoblast.