Cytokine suppressive anti-inflammatory compounds inhibit bone resorption in vitro.
Data from several laboratories suggest a role for a variety of cytokines in the process of bone resorption. SK&F 86002 [5-(4-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo(2,1-b) thiazole], a potent cytokine-suppressive anti-inflammatory agent, has been shown to inhibit cyclooxygenase (CO) and 5-lipoxygenase (LO) activity and to inhibit the production of cytokines both in vitro and in vivo. In the present study, SK&F 86002 inhibited fetal rat long bone (FRLB) resorption induced by parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D3, tumor necrosis factor alpha, and Escherichia coli lipopolysaccharide in a dose-dependent (IC50 of 0.5-1 microM) and reversible manner. Under identical conditions, selective CO inhibitors (indomethacin, ibuprofen, naproxen) and 5-LO inhibitors (phenidone, SK&F 107649) were inactive. Analogs of SK&F 86002, which are dual CO/LO inhibitors devoid of cytokine inhibitory activity (SK&F 81114 and SK&F 86055), also failed to significantly inhibit PTH-induced FRLB resorption. Analogs of SK&F 86002, which retain cytokine inhibitory activity (SK&F 104493 and SK&F 105561), inhibit bone resorption. These data indicate that the observed inhibition of bone resorption by compounds of this class correlates with their cytokine suppressive activity.
Votta
B J
BJ
Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA.
Bertolini
D R
DR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control*; D002117:Calcitriol / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000037:antagonists & inhibitors*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007375:Interleukin-1 / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000633:toxicity; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D010281:Parathyroid Hormone; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D017997:Leukotriene C4; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D002117:Calcitriol; D015232:Dinoprostone