文章基本信息

标题：Inhibition of Tumor Progression Locus 2 Protein Kinase Suppresses Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclastogenesis through Down-Regulation of the c-Fos and Nuclear Factor of Activated T Cells c1 Genes
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作者：Kazuya Hirata ; Hirofumi Taki ; Kouichiro Shinoda 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2010
卷号：33
期号：1
页码：133-137
DOI：10.1248/bpb.33.133
出版社：The Pharmaceutical Society of Japan
摘要：Whether tumor progression locus 2 (Tpl2)/cancer Osaka thyroid (Cot) protein kinase participates in osteoclastogenesis from receptor activator of nuclear factor-κB ligand (RANKL)-stimulated monocytes/macrophages remains elusive. To clarify this, a selective and potent inhibitor of Tpl2, 1,7-naphtyridine-3-carbonitrile, was used. When RAW264.7 cells were stimulated with RANKL, Tpl2 was found to be activated. Under this condition, the Tpl2 inhibitor suppressed osteoclastogenesis in a dose-dependent manner. This was due to the blockade of the phosphorylation of mitogen activated protein kinase/ERK kinase (MEK) and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK) or p38, concomitant with the down-regulation of the c-Fos and nuclear factor of activated T cells (NFAT)c1 genes. A long period of RANKL-stimulated cell exposure to the inhibitor suppressed osteoclastogenesis as assessed by tartrate-resistant acid phosphatase (TRAP) staining and pit formation on dentin slices. Almost identical results were obtained with macrophage colony-stimulating factor (M-CSF) and RANKL-stimulated bone marrow cells. These findings suggest the possibility that Tpl2 plays a pivotal role in osteoclastogenesis and thus that its inhibitor is useful for investigating the differentiation of monocytes/macrophages to osteoclasts after treatment with RANKL or other stimuli.
关键词：tumor progression locus 2;receptor activator of nuclear factor-κB ligand;c-Fos;nuclear factor of activated T cells c1;osteoclastogenesis