The Paired-box Homeodomain Transcription Factor Pax6 Binds to the Upstream Region of the TRAP Gene Promoter and Suppresses Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation

Kogawa, Masakazu; Hisatake, Koji; Atkins, Gerald J.; Findlay, David M.; Enoki, Yuichiro; Sato, Tsuyoshi; Gray, Peter C.; Kanesaki-Yatsuka, Yukiko; Anderson, Paul; Wada, Seiki; Kato, Naoki; Fukuda, Aya; Katayama, Shigehiro; Tsujimoto, Masafumi; Yoda, Tetsuya; Suda, Toshio; Okazaki, Yasushi; Matsumoto, Masahito

doi:10.1074/jbc.m113.461848

Cited by 19 publications

(15 citation statements)

References 66 publications

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“…In addition to these roles, we found that Pax6 is induced during osteoclastogenesis and that silencing of Pax6 promoted OC differentiation by enhancing the nuclear translocation of NFATc1. These results are partially consistent with the previous study (16). Unexpectedly, our data showed that Pax6 was up-regulated after treatment with VX-745 (p38 inhibitor), along with decreased expression of c-Fos and NFATc1.…”

Section: Discussionsupporting

confidence: 93%

“…Interestingly, another key gene of the Pax gene family, Pax6, is reportedly a negative regulator in RANKL-induced osteoclastogenesis. Pax6 can attenuate primary OC differentiation and promoter activity of the NFATc1mediated activation of Acp5 gene (16). This regulation of osteoclastogenesis is similar to RANKL-induced activation of the IFN-b or IFN-g gene, which constitutes a critical aspect of the negative feedback regulation of RANKL signaling for preventing excessive bone resorption (17).…”

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confidence: 96%

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Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

et al. 2018

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Balance of osteoclast formation is regulated by the receptor activator of NF‐κB ligand and extracellular negative regulators such as IFN‐γ and IFN‐β. However, very little is known about the intrinsic negative regulatory factors of osteoclast differentiation. Recently, the paired‐box homeodomain transcription factor Pax6 was shown to negatively regulate receptor activator of NF‐κB ligand‐mediated osteoclast differentiation. However, the mechanism underlying this regulation is still unclear. In this study, we show that a p38 inhibitor (VX‐745) up‐regulates the expression of Pax6 during osteoclast differentiation. Subsequently, we found that β‐catenin could bind to the proximal region of Pax6 promoter to induce its expression, and this action could be impaired by p38‐induced ubiquitin‐mediated degradation of β‐catenin. Our results suggest that Pax6 is regulated by a novel p38/β‐catenin pathway. Pax6 can further regulate the nuclear translocation of NF of activated T cells, cytoplasmic 1. Our study indicates that this novel p38/β‐catenin/Pax6 axis contributes to negative regulation of osteoclastogenesis. In addition, our study proposes a novel approach to treat osteoclast‐related diseases through the use of VX‐745 complemented with the β‐catenin activator SKL2001.—Jie, Z., Shen, S., Zhao, X., Xu, W., Zhang, X., Huang B., Tang P., Qin, A., Fan, S., Xie, Z. Activating β‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK. FASEB J. 33, 4236–4247 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

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confidence: 96%

Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

et al. 2018

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“…In vitro osteoclastogenesis assays were preformed to examine the effects of AP on osteoclast differentiation. Bone marrow macrophages (BMM) cells were prepared as previously described (Qin et al ., 2012b; Kogawa et al ., ; Zou et al ., ). Briefly, cells extracted from the femur and tibiae of a 6‐week‐old C57/BL6 mouse were incubated in complete cell culture media and 30 ng·mL −1 M‐CSF in a T‐75 cm 2 flask for proliferation.…”

Section: Methodsmentioning

confidence: 99%

Andrographolide suppresses RANKL‐induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo

Zhai

Liu

et al. 2014

British J Pharmacology

102

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Background and Purpose Osteoclasts play a pivotal role in diseases such as osteoporosis, rheumatoid arthritis and tumour bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast‐related diseases. Here, we examined changes in osteoclastogenesis and LPS‐induced osteolysis in response to andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata. Experimental Approach Effects of AP on osteoclast differentiation and bone resorption were measured in vitro. Western blots and RT‐PCR techniques were used to examine the underlying molecular mechanisms. The bone protective activity of AP in vivo was assessed in a mouse model of osteolysis. Key Results AP concentration‐dependently suppressed RANKL‐mediated osteoclast differentiation and bone resorption in vitro and reduced the expression of osteoclast‐specific markers, including tartrate‐resistant acid phosphatase, calcitonin receptors and cathepsin K. Further molecular analysis revealed that AP impaired RANKL‐induced NF‐κB signalling by inhibiting the phosphorylation of TGF‐β‐activated kinase 1, suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the nuclear translocation of the NF‐κB p65 subunit. AP also inhibited the ERK/MAPK signalling pathway without affecting p38 or JNK signalling. Conclusions and Implications AP suppressed RANKL‐induced osteoclastogenesis through attenuating NF‐κB and ERK/MAPK signalling pathways in vitro, thus preventing bone loss in vivo. These data indicated that AP is a promising natural compound for the treatment of osteoclast‐related bone diseases.

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“…The results demonstrated that PF alleviated joint destruction by decreasing the number of osteoclasts, leading to disease amelioration in CIA. TRAP, cathepsin and MMP‐9 are typical genes of osteoclast lineage. The expression of osteoclastogenesis‐related genes like TRAP and MMP‐9 was down‐regulated in the pathogenic sites of PF‐treated CIA mice, which is in accordance with osteoclast reduction.…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin ameliorates collagen‐induced arthritis via suppressing nuclear factor‐κB signalling pathway in osteoclast differentiation

Cai

Zhang

et al. 2018

Immunology

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Paeoniflorin (PF), extracted from the root of Paeonia lactiflora Pall, exhibits anti-inflammatory properties in several autoimmune diseases. Osteoclast, the only somatic cell with bone resorbing capacity, was the direct cause of bone destruction in rheumatoid arthritis (RA) and its mouse model, collagen-induced arthritis (CIA). The objective of this study was to estimate the effect of PF on CIA mice, and explore the mechanism of PF in bone destruction. We demonstrated that PF treatment significantly ameliorated CIA through inflammatory response inhibition and bone destruction suppression. Furthermore, PF treatment markedly decreased osteoclast number through the altered RANKL/RANK/OPG ratio and inflammatory cytokines profile. Consistently, we found that osteoclast differentiation was significantly inhibited by PF through down-regulation of nuclear factor-κB activation in vitro. Moreover, we found that PF suppressed nuclear factor-κB activation by decreasing its translocation to the nucleus in osteoclast precursor cells. Taken together, our new findings provide insights into a novel function of PF in osteoclastogenesis and demonstrate that PF would be a new therapeutic modality as a natural agent for RA treatment and other autoimmune conditions with bone erosion.

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The Paired-box Homeodomain Transcription Factor Pax6 Binds to the Upstream Region of the TRAP Gene Promoter and Suppresses Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation

Cited by 19 publications

References 66 publications

Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

Andrographolide suppresses RANKL‐induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo

Paeoniflorin ameliorates collagen‐induced arthritis via suppressing nuclear factor‐κB signalling pathway in osteoclast differentiation

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