Alendronate/interleukin-1beta 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-1beta (IL-1beta). Bone mass was quantitated at the end of the culture period to assess resorption. IL-6 was determined by bioassay (7TD1 cell proliferation). IL-1beta (18 and 180 pM) stimulated bone resorption and increased IL-6. Alendronate (70 microM) inhibited the IL-1beta-stimulated resorption. Alendronate alone did not affect IL-6 production by the bones. The IL-6 production from bones stimulated with 18 pM IL-1beta was not significantly affected by alendronate, but the IL-6 production from bones stimulated with 180 pM IL-1beta plus alendronate (21 and 70 microM) was higher than with IL-1beta alone. Indomethacin (1 mM) inhibited the IL-6 increase elicited by 180 pM IL-1beta and the enhanced IL-6 production elicited by cotreatment with IL-1beta and alendronate. Since bone cultures contain multiple cell types, further experiments were carried out to determine whether alendronate could increase IL-1beta-stimulated IL-6 production in an osteoblast cell line, UMR-106. Alendronate alone did not affect IL-6 in UMR-106 cells. Alendronate (70 microM) in combination with IL-1beta (180, 1.8, or 8 nM), or 7 microM alendronate, in combination with 8 nM IL-1beta, 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 by higher concentrations of the cytokine IL-1beta 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.
Sanders
J L
JL
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Tarjan
G
G
Foster
S A
SA
Stern
P H
PH
D019386:Alendronate / Q000008:administration & dosage*; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects* / Q000276:immunology*; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000096:biosynthesis*; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051381:Rats
D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D019386:Alendronate; D007213:Indomethacin