Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts

Takayanagi, Hiroshi; Kim, Sun-Hwa; Koga, Tatsuya; Nishina, Hiroshi; Isshiki, Masashi; Yoshida, Hiroki; Saiura, Akio; Isobe, Miho; Yokochi, Taeko; Inoue, Jun‐ichiro; Wagner, Erwin F.; Mak, Tak W.; Kodama, Tatsuhiko; Taniguchi, Tadatsugu

doi:10.1016/s1534-5807(02)00369-6

Cited by 2,266 publications

(2,568 citation statements)

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“…JNK1 activated by RANKL protects osteoclast precursors from RANKL-induced apoptosis and regulates osteoclastogenesis through the phosphorylation of c-Jun, a component of the dimeric transcription factor AP-1 [25]. C-Fos, another component of AP-1, is an essential transcription factor for osteoclast differentiation [21,22,26]. Up-regulation of c-Fos by the p38 pathway has been recently reported [27].…”

Section: Discussionmentioning

confidence: 99%

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The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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The 4-1BB is a costimulatory molecule similar to the receptor activator of NF-jB ligand (RANKL), both of which are key factors for the differentiation of osteoclasts and are expressed mainly by activated T cells. The 4-1BB shares common signaling pathways with RANK, suggesting a potential role in osteoclastogenesis. In this study, the role of 4-1BB and 4-1BB ligand (4-1BBL) in osteoclastogenesis was investigated using 4-1BB -/-and 4-1BB +/+ mice. Osteoclast precursors normally express 4-1BB and 4-1BBL after exposure to RANKL, which was confirmed by semi-quantitative RT-PCR and flow cytometry. The 4-1BB -/-mice had a slightly increased bone mass accompanied by a reduced osteoclastogenic ability of 4-1BB -/-bone marrow-derived macrophages (BMM) ex vivo. In addition, 4-1BB -/-BMM demonstrated hypophosphorylation of JNK and p38 and decreased induction of c-Fos in response to RANKL stimulation. Retroviral transduction of wild-type as well as partiallength 4-1BB, which lacks TNF receptor-associated factor 2-binding sites for signaling, restored the osteoclastogenic ability of 4-1BB -/-BMM. Furthermore, both recombinant 4-1BB and 4-1BBL enhanced RANKL-induced osteoclastogenesis by 4-1BB +/+ BMM and the induction of c-Fos and NFATc1.Together, these results indicate that 4-1BBL and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling, findings that may delineate the complex nature of the 4-1BBL and 4-1BB interaction.

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Section: Discussionmentioning

confidence: 99%

“…RANKL stimulation also induces the expression of c-Fos and NFATc1, essential transcription factors in RANKL-induced osteoclastogenesis [21,22]. Thus, we used sqRT-PCR to examine the expression of c-Fos and NFATc1 during RANKL-mediated osteoclastogenesis.…”

Section: Decreased Osteoclastogenic Ability Of 4-1bb -/-Bmm Ex Vivomentioning

confidence: 99%

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

et al. 2008

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“…*p \ 0.01, **p \ 0.05 specifically stimulated, and IjB signals. And costimulatory immunoreceptors lead to the robust induction of NFATc1, which is a necessary and sufficient factor for osteoclast differentiation (Takayanagi 2007;Walsh et al 2006;Takayanagi 2005Takayanagi , 2002Asagiri et al 2005). We examined whether luteolin could modulate the expressions of these genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of luteolin on osteoclast differentiation and function

et al. 2009

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Osteoclasts are multinucleated cells that play a crucial role in bone resorption, and are formed by the fusion of mononuclear osteoclasts derived from osteoclast precursors of the macrophage lineage. Compounds that specifically target functional osteoclasts would be ideal candidates for anti-resorptive agents for clinical applications. In the present study, we investigated the effects of luteolin, a flavonoid, on the regulation of receptor activator of nuclear factorjB ligand (RANKL)-induced osteoclastogenesis, functions and signaling pathway. Addition of luteolin to a coculture system of mouse bone marrow cells and ST2 cells in the presence of 10 -8 M 1a,25(OH) 2 D 3 caused significant inhibition of osteoclastogenesis. Luteolin had no effects on the 1a,25(OH) 2 D 3 -induced expressions of RANKL, osteoprotegerin and macrophage colony-stimulating factor mRNAs. Next, we examined the direct effects of luteolin on osteoclast precursors using bone marrow macrophages and RAW264.7 cells. Luteolin completely inhibited RANKL-induced osteoclast formation. Moreover, luteolin inhibited the bone resorption by mature osteoclasts accompanied by the disruption of their actin rings, and these effects were reversely induced by the disruption of the actin rings in mature osteoclasts. Finally, we found that luteolin inhibited RANKLinduced osteoclastogenesis through the suppression of ATF2, downstream of p38 MAPK and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) expression, respectively. Taken together, the present results indicate that naturally occurring luteolin has inhibitory activities toward both osteoclast differentiation and functions through inhibition of RANKL-induced signaling pathway as well as actin ring disruption, respectively.

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“…The TRAF-binding domains of RANK are important for the RANK-dependent induction of NF-B and JNK (21,23). In addition, the signaling pathways via the transcription factors c-Fos and nuclear factor of activated T cells c1 (NF-ATc1) seem to be important for RANKL-induced osteoclastogenesis, as outlined in recent studies (24)(25)(26). RANKL also activates the antiapoptotic serine/ threonine kinase protein kinase B/Akt through a signaling complex involving c-Src and TRAF6, which interact with one another and with RANK after receptor engagement (27).…”

mentioning

confidence: 92%

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Neumann

Müller‐Ladner

2005

Arthritis & Rheumatism

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Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts

Cited by 2,266 publications

References 59 publications

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

The 4–1BB ligand and 4–1BB expressed on osteoclast precursors enhance RANKL‐induced osteoclastogenesis via bi‐directional signaling

Inhibitory effect of luteolin on osteoclast differentiation and function

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

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