Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation

Ikeda, Fumiyo; Nishimura, Riko; Matsubara, Takuma; Tanaka, Sakae; Inoue, Jun; Reddy, Sakamuri V.; Hata, Kenji; Yamashita, Kenji; Hiraga, Toru; Watanabe, Toshiyuki; Kukita, Toshio; Yoshioka, Katsuji; Rao, Anjana; Yoneda, Toshiyuki

doi:10.1172/jci19657

Cited by 258 publications

(285 citation statements)

References 43 publications

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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%

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%

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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“…It was shown that the expression of dominant-negative forms of p38 MAPK and MKK6 in RAW264.7 cells inhibited RANKL-induced differentiation of RAW264.7 cells into osteoclasts (Matsumoto et al 2000). Moreover, addition of luteolin to osteoclast cultures strongly inhibited the expression of NFATc1, which is a key transcription factor for the expressions of TRAP and other osteoclastogenesis-associated genes (Ikeda et al 2004;Matsumoto et al 2004;Sharma et al 2007). Therefore, the effects of luteolin on osteoclastogenesis are probably mediated by ATF2, downstream of p38 MAPK pathway.…”

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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“…8 It was suggested that JNK participates to Oc differentiation by playing a role in RANKL induction of NFATc1 expression through c-Jun activation. 9 Specific activation of JNK1, but not JNK2, by RANKL in bone marrow monocytes (Oc precursors) and selective requirement of JNK1, but not JNK2, activity for efficient OC differentiation were reported. 10 The involvement of p38 in osteoclastogenesis has been demonstrated by the treatment of bone marrow precursor cells with pharmacological inhibitors of the kinase.…”

Section: Introductionmentioning

confidence: 99%

“…The involvement of MKK7 in Oc differentiation from the precursors in spleen cells and from RAW264.7 cells was demonstrated by using a siRNA and DN form, respectively. 9,14 The expression of a DN form of MKK6 was shown to inhibit Oc differentiation form RAW264.7 cells. 13 Knowledge on the upstream kinases (MAPKKKs) that activate MKKs for Oc differentiation has remained limited.…”

Section: Introductionmentioning

confidence: 99%

Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL

et al. 2006

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Osteoclast (Oc) differentiation is fundamentally controlled by receptor activator of nuclear factor kappaB ligand (RANKL). RANKL signalling targets include mitogen-activated protein kinases (MAPKs), nuclear factor kappaB (NF-jB), and nuclear factor of activated T cells (NFAT)c1. In this study, we found that p38 MAPK upstream components transforming growth factor-beta-activated kinase 1 (TAK1), MKK3, and MKK6 increased by RANKL in an early stage of osteoclastogenesis from primary bone marrow cells, which led to enhanced p38 activation. Retroviral transduction of dominant-negative (DN) forms of TAK1 and MKK6, but not that of MKK3, reduced Oc differentiation. Transduction of TAK1-DN and MKK6-DN and treatment with the p38 inhibitor SB203580 attenuated NFATc1 induction by RANKL. TAK1-DN, MKK6-DN, and SB203580, but not MKK3-DN, also suppressed RANKL stimulation of NF-jB transcription activity in a manner dependent on p65 phosphorylation on Ser-536. These results indicate that TAK1 and MKK6 constitute the p38 signalling pathway to participate to Oc differentiation by RANKL through p65 phosphorylation and NFATc1 induction, and that MKK6 and MKK3 have differential roles in osteoclastogenesis from bone marrow precursors.

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Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation

Cited by 258 publications

References 43 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

Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL

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