Receptor activator of nuclear factor-kappaB is induced by a rottlerin-sensitive and p38 MAP kinase-dependent pathway during monocyte differentiation.
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.
Kang
Hong Soon
HS
Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Kyungpook National University, Daegu 700-412, Korea.
Park
Eui Kyun
EK
Kim
Kyung Hee
KH
Park
Ju-Young
JY
Choi
Je-Yong
JY
Shin
Hong-In
HI
Jun
Chang-Duk
CD
Kang
Shin-Sung
SS
Kim
Shin-Yoon
SY
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008301:Maleimides; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D053244:Osteoprotegerin; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051745:Protein Kinase C-delta; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D048051:p38 Mitogen-Activated Protein Kinases
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D000098:Acetophenones; D001578:Benzopyrans; D039481:CD11b Antigen; D002227:Carbazoles; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D053244:Osteoprotegerin; D010703:Phorbol Esters; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506031:Tnfrsf11b protein, mouse; D002762:Cholecalciferol; D016173:Macrophage Colony-Stimulating Factor; C085746:rottlerin; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580