The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I

Makoto Kawatani, Hideo Okumura, Kaori Honda, Naoki Kanoh, Makoto Muroi, Naoshi Dohmae, Masamichi Takami, Mitsuhiro Kitagawa, Yushi Futamura, Masaya Imoto, Hiroyuki Osada

研究成果: Article

95 引用 (Scopus)

抄録

Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.

元の言語English
ページ(範囲)11691-11696
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
105
発行部数33
DOI
出版物ステータスPublished - 2008 8 19

Fingerprint

Lactoylglutathione Lyase
Osteogenesis
Osteoclasts
Bone Density Conservation Agents
Pyruvaldehyde
4-carboxy-5,5'-dihydroxy-3,3'-dimethyl-diphenylether
Bone Diseases
Hematopoietic Stem Cells
Biological Products
Osteoporosis
Catalytic Domain
Carrier Proteins
Esters
Stem Cells
Bone and Bones

ASJC Scopus subject areas

  • Genetics
  • General

これを引用

The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I. / Kawatani, Makoto; Okumura, Hideo; Honda, Kaori; Kanoh, Naoki; Muroi, Makoto; Dohmae, Naoshi; Takami, Masamichi; Kitagawa, Mitsuhiro; Futamura, Yushi; Imoto, Masaya; Osada, Hiroyuki.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 105, 番号 33, 19.08.2008, p. 11691-11696.

研究成果: Article

Kawatani, M, Okumura, H, Honda, K, Kanoh, N, Muroi, M, Dohmae, N, Takami, M, Kitagawa, M, Futamura, Y, Imoto, M & Osada, H 2008, 'The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I', Proceedings of the National Academy of Sciences of the United States of America, 巻. 105, 番号 33, pp. 11691-11696. https://doi.org/10.1073/pnas.0712239105
Kawatani, Makoto ; Okumura, Hideo ; Honda, Kaori ; Kanoh, Naoki ; Muroi, Makoto ; Dohmae, Naoshi ; Takami, Masamichi ; Kitagawa, Mitsuhiro ; Futamura, Yushi ; Imoto, Masaya ; Osada, Hiroyuki. / The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I. :: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; 巻 105, 番号 33. pp. 11691-11696.
@article{a6704861bc774bc5858b2c16f4d459be,
title = "The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I",
abstract = "Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.",
keywords = "Crystal structure, Osteoclast, Small molecule",
author = "Makoto Kawatani and Hideo Okumura and Kaori Honda and Naoki Kanoh and Makoto Muroi and Naoshi Dohmae and Masamichi Takami and Mitsuhiro Kitagawa and Yushi Futamura and Masaya Imoto and Hiroyuki Osada",
year = "2008",
month = "8",
day = "19",
doi = "10.1073/pnas.0712239105",
language = "English",
volume = "105",
pages = "11691--11696",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",

}

TY - JOUR

T1 - The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I

AU - Kawatani, Makoto

AU - Okumura, Hideo

AU - Honda, Kaori

AU - Kanoh, Naoki

AU - Muroi, Makoto

AU - Dohmae, Naoshi

AU - Takami, Masamichi

AU - Kitagawa, Mitsuhiro

AU - Futamura, Yushi

AU - Imoto, Masaya

AU - Osada, Hiroyuki

PY - 2008/8/19

Y1 - 2008/8/19

N2 - Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.

AB - Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.

KW - Crystal structure

KW - Osteoclast

KW - Small molecule

UR - http://www.scopus.com/inward/record.url?scp=50149114458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50149114458&partnerID=8YFLogxK

U2 - 10.1073/pnas.0712239105

DO - 10.1073/pnas.0712239105

M3 - Article

C2 - 18695250

AN - SCOPUS:50149114458

VL - 105

SP - 11691

EP - 11696

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 33

ER -