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-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.
Hirata
Kazuya
K
Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan. hirata.kazuya@me.mt-pharma.co.jp
Taki
Hirofumi
H
Shinoda
Kouichiro
K
Hounoki
Hiroyuki
H
Miyahara
Tatsuro
T
Tobe
Kazuyuki
K
Ogawa
Hirofumi
H
Mori
Hisashi
H
Sugiyama
Eiji
E
D000135:Acid Phosphatase; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D003804:Dentin; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015870:Gene Expression; D016762:Genes, fos; D007527:Isoenzymes; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase
D007527:Isoenzymes; D008024:Ligands; D050778:NFATC Transcription Factors; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase