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Inhibition of tumor progression locus 2 protein kinase suppresses receptor activator of nuclear factor-kappaB ligand-induced osteoclastogenesis through down-regulation of the c-Fos and nuclear factor of activated T cells c1 genes

Whether tumor progression locus 2 (Tpl2)/cancer Osaka thyroid (Cot) protein kinase participates in osteoclastogenesis from receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated monocytes/macrophages remains elusive. To clarify this, a selective and potent inhibitor of Tpl2, 1,7-napht...

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Published in:Biological & pharmaceutical bulletin 2010, Vol.33 (1), p.133-137
Main Authors: Hirata, Kazuya, Taki, Hirofumi, Shinoda, Kouichiro, Hounoki, Hiroyuki, Miyahara, Tatsuro, Tobe, Kazuyuki, Ogawa, Hirofumi, Mori, Hisashi, Sugiyama, Eiji
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Language:English
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Summary:Whether tumor progression locus 2 (Tpl2)/cancer Osaka thyroid (Cot) protein kinase participates in osteoclastogenesis from receptor activator of nuclear factor-kappaB 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.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.33.133