Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-κB inhibitor, through downregulation of NFATc1

Hiroshi Takatsuna, Masataka Asagiri, Takeshi Kubota, Kotaro Oka, Toshihiro Osada, Chie Sugiyama, Hiroaki Saito, Kazuhiro Aoki, Keiichi Ohya, Hiroshi Takayanagi, Kazuo Umezawa

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107 Citations (Scopus)

Abstract

(-)-DHMEQ, a newly designed NF-κB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. Introduction: Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-κB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-κB result in impaired osteoclastogenesis, but how NF-κB is involved in the regulation of osteoclastogenesis is not known. Materials and Methods: The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. Results: (-)-DHMEQ strongly inhibited RANKL-induced NF-κB activation in BMMs and inhibited RANKL-induced formation of TRACP+ multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. Conclusion: The inhibition of NF-κB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-κB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.

Original languageEnglish
Pages (from-to)653-662
Number of pages10
JournalJournal of Bone and Mineral Research
Volume20
Issue number4
DOIs
Publication statusPublished - 2005 Apr

Fingerprint

Osteogenesis
Down-Regulation
Osteoclasts
Bone and Bones
Monocyte-Macrophage Precursor Cells
TNF Receptor-Associated Factor 6
Macrophage Colony-Stimulating Factor
Poisons
Multiple Myeloma
Immunoblotting
Rheumatoid Arthritis
Transcription Factors
Macrophages
Pharmacology

Keywords

  • Bone resorption
  • NF-κB
  • NFATc1
  • Osteoclastogenesis
  • RANKL

ASJC Scopus subject areas

  • Surgery

Cite this

Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-κB inhibitor, through downregulation of NFATc1. / Takatsuna, Hiroshi; Asagiri, Masataka; Kubota, Takeshi; Oka, Kotaro; Osada, Toshihiro; Sugiyama, Chie; Saito, Hiroaki; Aoki, Kazuhiro; Ohya, Keiichi; Takayanagi, Hiroshi; Umezawa, Kazuo.

In: Journal of Bone and Mineral Research, Vol. 20, No. 4, 04.2005, p. 653-662.

Research output: Contribution to journalArticle

Takatsuna, H, Asagiri, M, Kubota, T, Oka, K, Osada, T, Sugiyama, C, Saito, H, Aoki, K, Ohya, K, Takayanagi, H & Umezawa, K 2005, 'Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-κB inhibitor, through downregulation of NFATc1', Journal of Bone and Mineral Research, vol. 20, no. 4, pp. 653-662. https://doi.org/10.1359/JBMR.041213
Takatsuna, Hiroshi ; Asagiri, Masataka ; Kubota, Takeshi ; Oka, Kotaro ; Osada, Toshihiro ; Sugiyama, Chie ; Saito, Hiroaki ; Aoki, Kazuhiro ; Ohya, Keiichi ; Takayanagi, Hiroshi ; Umezawa, Kazuo. / Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-κB inhibitor, through downregulation of NFATc1. In: Journal of Bone and Mineral Research. 2005 ; Vol. 20, No. 4. pp. 653-662.
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abstract = "(-)-DHMEQ, a newly designed NF-κB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. Introduction: Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-κB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-κB result in impaired osteoclastogenesis, but how NF-κB is involved in the regulation of osteoclastogenesis is not known. Materials and Methods: The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. Results: (-)-DHMEQ strongly inhibited RANKL-induced NF-κB activation in BMMs and inhibited RANKL-induced formation of TRACP+ multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. Conclusion: The inhibition of NF-κB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-κB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.",
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AU - Kubota, Takeshi

AU - Oka, Kotaro

AU - Osada, Toshihiro

AU - Sugiyama, Chie

AU - Saito, Hiroaki

AU - Aoki, Kazuhiro

AU - Ohya, Keiichi

AU - Takayanagi, Hiroshi

AU - Umezawa, Kazuo

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N2 - (-)-DHMEQ, a newly designed NF-κB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. Introduction: Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-κB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-κB result in impaired osteoclastogenesis, but how NF-κB is involved in the regulation of osteoclastogenesis is not known. Materials and Methods: The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. Results: (-)-DHMEQ strongly inhibited RANKL-induced NF-κB activation in BMMs and inhibited RANKL-induced formation of TRACP+ multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. Conclusion: The inhibition of NF-κB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-κB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.

AB - (-)-DHMEQ, a newly designed NF-κB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. Introduction: Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-κB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-κB result in impaired osteoclastogenesis, but how NF-κB is involved in the regulation of osteoclastogenesis is not known. Materials and Methods: The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. Results: (-)-DHMEQ strongly inhibited RANKL-induced NF-κB activation in BMMs and inhibited RANKL-induced formation of TRACP+ multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. Conclusion: The inhibition of NF-κB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-κB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.

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