Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis

Hiroko Hoshi, Wu Hao, Yoshinari Fujita, Atsushi Funayama, Yoshiteru Miyauchi, Kazuaki Hashimoto, Kana Miyamoto, Ryotaro Iwasaki, Yuiko Sato, Tami Kobayashi, Hiroya Miyamoto, Shigeyuki Yoshida, Tomoaki Mori, Hiroya Kanagawa, Eri Katsuyama, Atsuhiro Fujie, Kyoko Kitagawa, Keiichi I. Nakayama, Toshihiro Kawamoto, Motoaki SanoKeiichi Fukuda, Ikuroh Ohsawa, Shigeo Ohta, Hideo Morioka, Morio Matsumoto, Kazuhiro Chiba, Yoshiaki Toyama, Takeshi Miyamoto

研究成果: ジャーナルへの寄稿記事

27 引用 (Scopus)

抄録

Osteoporosis is a complex disease with various causes, such as estrogen loss, genetics, and aging. Here we show that a dominant-negative form of aldehyde dehydrogenase 2 (ALDH2) protein, ALDH2*2, which is produced by a single nucleotide polymorphism (rs671), promotes osteoporosis due to impaired osteoblastogenesis. Aldh2 plays a role in alcohol-detoxification by acetaldehyde-detoxification; however, transgenic mice expressing Aldh2*2 (Aldh2*2 Tg) exhibited severe osteoporosis with increased levels of blood acetaldehyde without alcohol consumption, indicating that Aldh2 regulates physiological bone homeostasis. Wild-type osteoblast differentiation was severely inhibited by exogenous acetaldehyde, and osteoblastic markers such as osteocalcin, runx2, and osterix expression, or phosphorylation of Smad1,5,8 induced by bone morphogenetic protein 2 (BMP2) was strongly altered by acetaldehyde. Acetaldehyde treatment also inhibits proliferation and induces apoptosis in osteoblasts. The Aldh2*2 transgene or acetaldehyde treatment induced accumulation of the lipid-oxidant 4-hydroxy-2-nonenal (4HNE) and expression of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that promotes adipogenesis and inhibits osteoblastogenesis. Antioxidant treatment inhibited acetaldehyde-induced proliferation-loss, apoptosis, and PPARγ expression and restored osteoblastogenesis inhibited by acetaldehyde. Treatment with a PPARγ inhibitor also restored acetaldehyde-mediated osteoblastogenesis inhibition. These results provide new insight into regulation of osteoporosis in a subset of individuals with ALDH2*2 and in alcoholic patients and suggest a novel strategy to promote bone formation in such osteopenic diseases.

元の言語英語
ページ(範囲)2015-2023
ページ数9
ジャーナルJournal of Bone and Mineral Research
27
発行部数9
DOI
出版物ステータス出版済み - 9 1 2012

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Acetaldehyde
Aldehydes
Osteoporosis
Mutation
Aldehyde Dehydrogenase
PPAR gamma
Osteoblasts
Apoptosis
Adipogenesis
Bone Morphogenetic Protein 2
Osteocalcin
Therapeutics
Alcoholics
Transgenes
Oxidants
Osteogenesis
Alcohol Drinking
Transgenic Mice
Single Nucleotide Polymorphism
Estrogens

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

これを引用

Hoshi, H., Hao, W., Fujita, Y., Funayama, A., Miyauchi, Y., Hashimoto, K., ... Miyamoto, T. (2012). Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. Journal of Bone and Mineral Research, 27(9), 2015-2023. https://doi.org/10.1002/jbmr.1634

Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. / Hoshi, Hiroko; Hao, Wu; Fujita, Yoshinari; Funayama, Atsushi; Miyauchi, Yoshiteru; Hashimoto, Kazuaki; Miyamoto, Kana; Iwasaki, Ryotaro; Sato, Yuiko; Kobayashi, Tami; Miyamoto, Hiroya; Yoshida, Shigeyuki; Mori, Tomoaki; Kanagawa, Hiroya; Katsuyama, Eri; Fujie, Atsuhiro; Kitagawa, Kyoko; Nakayama, Keiichi I.; Kawamoto, Toshihiro; Sano, Motoaki; Fukuda, Keiichi; Ohsawa, Ikuroh; Ohta, Shigeo; Morioka, Hideo; Matsumoto, Morio; Chiba, Kazuhiro; Toyama, Yoshiaki; Miyamoto, Takeshi.

:: Journal of Bone and Mineral Research, 巻 27, 番号 9, 01.09.2012, p. 2015-2023.

研究成果: ジャーナルへの寄稿記事

Hoshi, H, Hao, W, Fujita, Y, Funayama, A, Miyauchi, Y, Hashimoto, K, Miyamoto, K, Iwasaki, R, Sato, Y, Kobayashi, T, Miyamoto, H, Yoshida, S, Mori, T, Kanagawa, H, Katsuyama, E, Fujie, A, Kitagawa, K, Nakayama, KI, Kawamoto, T, Sano, M, Fukuda, K, Ohsawa, I, Ohta, S, Morioka, H, Matsumoto, M, Chiba, K, Toyama, Y & Miyamoto, T 2012, 'Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis', Journal of Bone and Mineral Research, 巻. 27, 番号 9, pp. 2015-2023. https://doi.org/10.1002/jbmr.1634
Hoshi, Hiroko ; Hao, Wu ; Fujita, Yoshinari ; Funayama, Atsushi ; Miyauchi, Yoshiteru ; Hashimoto, Kazuaki ; Miyamoto, Kana ; Iwasaki, Ryotaro ; Sato, Yuiko ; Kobayashi, Tami ; Miyamoto, Hiroya ; Yoshida, Shigeyuki ; Mori, Tomoaki ; Kanagawa, Hiroya ; Katsuyama, Eri ; Fujie, Atsuhiro ; Kitagawa, Kyoko ; Nakayama, Keiichi I. ; Kawamoto, Toshihiro ; Sano, Motoaki ; Fukuda, Keiichi ; Ohsawa, Ikuroh ; Ohta, Shigeo ; Morioka, Hideo ; Matsumoto, Morio ; Chiba, Kazuhiro ; Toyama, Yoshiaki ; Miyamoto, Takeshi. / Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. :: Journal of Bone and Mineral Research. 2012 ; 巻 27, 番号 9. pp. 2015-2023.
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abstract = "Osteoporosis is a complex disease with various causes, such as estrogen loss, genetics, and aging. Here we show that a dominant-negative form of aldehyde dehydrogenase 2 (ALDH2) protein, ALDH2*2, which is produced by a single nucleotide polymorphism (rs671), promotes osteoporosis due to impaired osteoblastogenesis. Aldh2 plays a role in alcohol-detoxification by acetaldehyde-detoxification; however, transgenic mice expressing Aldh2*2 (Aldh2*2 Tg) exhibited severe osteoporosis with increased levels of blood acetaldehyde without alcohol consumption, indicating that Aldh2 regulates physiological bone homeostasis. Wild-type osteoblast differentiation was severely inhibited by exogenous acetaldehyde, and osteoblastic markers such as osteocalcin, runx2, and osterix expression, or phosphorylation of Smad1,5,8 induced by bone morphogenetic protein 2 (BMP2) was strongly altered by acetaldehyde. Acetaldehyde treatment also inhibits proliferation and induces apoptosis in osteoblasts. The Aldh2*2 transgene or acetaldehyde treatment induced accumulation of the lipid-oxidant 4-hydroxy-2-nonenal (4HNE) and expression of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that promotes adipogenesis and inhibits osteoblastogenesis. Antioxidant treatment inhibited acetaldehyde-induced proliferation-loss, apoptosis, and PPARγ expression and restored osteoblastogenesis inhibited by acetaldehyde. Treatment with a PPARγ inhibitor also restored acetaldehyde-mediated osteoblastogenesis inhibition. These results provide new insight into regulation of osteoporosis in a subset of individuals with ALDH2*2 and in alcoholic patients and suggest a novel strategy to promote bone formation in such osteopenic diseases.",
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AU - Miyauchi, Yoshiteru

AU - Hashimoto, Kazuaki

AU - Miyamoto, Kana

AU - Iwasaki, Ryotaro

AU - Sato, Yuiko

AU - Kobayashi, Tami

AU - Miyamoto, Hiroya

AU - Yoshida, Shigeyuki

AU - Mori, Tomoaki

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AU - Sano, Motoaki

AU - Fukuda, Keiichi

AU - Ohsawa, Ikuroh

AU - Ohta, Shigeo

AU - Morioka, Hideo

AU - Matsumoto, Morio

AU - Chiba, Kazuhiro

AU - Toyama, Yoshiaki

AU - Miyamoto, Takeshi

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