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.