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Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1.
J Bone Miner Res. 2005 Apr; 20(4):653-62.JB

Abstract

(-)-DHMEQ, a newly designed NF-kappaB 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-kappaB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-kappaB result in impaired osteoclastogenesis, but how NF-kappaB 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-kappaB 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-kappaB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-kappaB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.

Authors+Show Affiliations

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15765185

Citation

Takatsuna, Hiroshi, et al. "Inhibition of RANKL-induced Osteoclastogenesis By (-)-DHMEQ, a Novel NF-kappaB Inhibitor, Through Downregulation of NFATc1." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 20, no. 4, 2005, pp. 653-62.
Takatsuna H, Asagiri M, Kubota T, et al. Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1. J Bone Miner Res. 2005;20(4):653-62.
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-kappaB inhibitor, through downregulation of NFATc1. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 20(4), 653-62.
Takatsuna H, et al. Inhibition of RANKL-induced Osteoclastogenesis By (-)-DHMEQ, a Novel NF-kappaB Inhibitor, Through Downregulation of NFATc1. J Bone Miner Res. 2005;20(4):653-62. PubMed PMID: 15765185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1. AU - Takatsuna,Hiroshi, AU - Asagiri,Masataka, 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, Y1 - 2004/12/06/ PY - 2004/09/18/received PY - 2004/10/29/revised PY - 2004/11/17/accepted PY - 2005/3/15/pubmed PY - 2005/12/13/medline PY - 2005/3/15/entrez SP - 653 EP - 62 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 20 IS - 4 N2 - UNLABELLED: (-)-DHMEQ, a newly designed NF-kappaB 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-kappaB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-kappaB result in impaired osteoclastogenesis, but how NF-kappaB 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-kappaB 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-kappaB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-kappaB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/15765185/Inhibition_of_RANKL_induced_osteoclastogenesis_by_____DHMEQ_a_novel_NF_kappaB_inhibitor_through_downregulation_of_NFATc1_ L2 - https://doi.org/10.1359/JBMR.041213 DB - PRIME DP - Unbound Medicine ER -