Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis
Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis
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DOI：
10.1002/jbmr.1634
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发表时间：
2012-09-01
影响因子：
6.2
通讯作者：
Miyamoto, Takeshi
中科院分区：
文献类型：
--
作者：
Hoshi, Hiroko;Hao, Wu;Miyamoto, Takeshi
骨质疏松症是一种复杂的疾病，有多种原因，如雌激素丢失、遗传和衰老。在这里，我们展示了由单核苷酸多态(Rs671)产生的显性-阴性形式的乙醛脱氢酶2(ALDH2*2)蛋白，它促进了由于成骨细胞形成障碍而导致的骨质疏松症。ALDH2通过乙醛解毒在酒精解毒中发挥作用；然而，表达ALDH2*2(ALDH2*2 TG)的转基因小鼠在不饮酒的情况下表现出严重的骨质疏松症，血中乙醛水平增加，表明ALDH2调节生理性骨平衡。外源性乙醛严重抑制野生型成骨细胞分化，并强烈改变成骨标志物如骨钙素、Runx2和Osterix的表达，或骨形态发生蛋白2(BMP2)诱导的Smad1、5、8的磷酸化。乙醛处理还可抑制成骨细胞的增殖并诱导其凋亡。ALDH2*2转基因或乙醛处理可诱导脂质氧化剂4-羟基-2-壬烯醛(4HNE)的积聚和PPAR？的表达，PPAR？是一种促进脂肪生成和抑制成骨细胞生成的转录因子。抗氧化剂处理可抑制乙醛诱导的细胞增殖丢失、细胞凋亡和PPAR？乙醛抑制成骨细胞表达和修复成骨细胞的作用。使用PPAR进行治疗？抑制剂能恢复乙醛介导的成骨细胞生成抑制作用。这些结果为ALDH2*2患者和酗酒患者的骨质疏松症的调节提供了新的见解，并建议了一种新的策略来促进此类骨质疏松疾病的骨形成。(C)2012年美国骨与矿物研究学会。
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. (c) 2012 American Society for Bone and Mineral Research.