title: Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis.
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.
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hoshi
authors.forename: Wu
authors.initials: W
authors.lastname: Hao
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Fujita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Funayama
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Miyauchi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Kana
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Iwasaki
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Sato
authors.forename: Tami
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hiroya
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mori
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kanagawa
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Fujie
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Ikuroh
authors.initials: I
authors.lastname: Ohsawa
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohta
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism* / Q000494:pharmacology; D050156:Adipogenesis / Q000187:drug effects; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000975:Antioxidants; C096127:ALDH2 protein, human; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde