cholecalciferol and rottlerin

Receptor activator of nuclear factor-kappaB (RANK) plays a central role in the regulation of osteoclast differentiation and activation, but the mechanisms underlying its expression remain to be elucidated. In the present study we showed that expression of RANK was strongly induced by phorbol-12-myristate-13-acetate (PMA) during monocyte differentiation of U937 cells, and was enhanced by concomitant treatment with vitamin D3. Induction was dramatically inhibited by protein kinase C (PKC) inhibitors such as rottlerin and Gö6983, but not by Gö6976. Interestingly, rottlerin, a selective inhibitor of PKCdelta, reduced PMA-induced RANK expression while having no effect on CD11b expression. However overexpression of wild type PKCdelta, or a kinase-inactive mutant, did not affect PMA-induction of RANK, suggesting that rottlerin inhibits PMA-induced expression of RANK via a PKCdelta-independent mechanism. Rottlerin also inhibited PMA-induced phosphorylation of p38 mitogen-activated protein kinase (p38MAPK), and the p38 MAPK inhibitor SB203580 inhibited induction of RANK. Rottlerin and SB203580 also substantially reduced RANK mRNA expression in mouse BMM cells stimulated with macrophage colony stimulating factor (M-CSF). Together, these results demonstrate that expression of RANK is dependent upon a rottlerin-sensitive and p38MAPK-dependent pathway during monocyte differentiation.

Topics: Acetophenones; Animals; Benzopyrans; Carbazoles; CD11b Antigen; Cell Differentiation; Cells, Cultured; Cholecalciferol; Enzyme Activation; Enzyme Inhibitors; Glycoproteins; Imidazoles; Indoles; Macrophage Colony-Stimulating Factor; Maleimides; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Monocytes; Osteoprotegerin; p38 Mitogen-Activated Protein Kinases; Phorbol Esters; Phosphorylation; Protein Kinase C; Protein Kinase C-delta; Pyridines; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor