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

作者：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^*

来源：Journal of Bone and Mineral Research, 2012, 27(9): 2015-2023.

DOI：10.1002/jbmr.1634

• ALDEHYDE DEHYDROGENASE 2
• OSTEOPOROSIS
• ACETALDEHYDE
• 4-HYDROXY-2-NONENAL
• OSTEOBLASTS

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 (PPAR?), a transcription factor that promotes adipogenesis and inhibits osteoblastogenesis. Antioxidant treatment inhibited acetaldehyde-induced proliferation-loss, apoptosis, and PPAR? expression and restored osteoblastogenesis inhibited by acetaldehyde. Treatment with a PPAR? 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.

• 出版日期2012-9