Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids
Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids
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DOI：
10.1074/jbc.m702810200
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发表时间：
2007-09-14
影响因子：
4.8
通讯作者：
Manolagas, Stavros C.
中科院分区：
文献类型：
--
作者：
Almeida, Maria;Han, Li;Manolagas, Stavros C.
衰老和性类固醇激素的减少都对骨骼稳态产生不利影响，但它们是否以及如何相互影响对骨骼的负面影响仍然未知。我们在此报告，雌性和雄性C57 BL/6小鼠逐渐失去力量（由负载失效测量）和骨密度在4和31个月的年龄之间的脊柱和股骨。这些变化与骨重建速率的降低有时间相关性，如成骨细胞和破骨细胞数量的减少和骨形成速率的降低所证明的;以及成骨细胞和骨细胞凋亡增加、活性氧水平增加、谷胱甘肽还原酶活性降低和p53和p66（SHC）磷酸化的相应增加，信号级联的两个关键组成部分，由活性氧激活并影响细胞凋亡和寿命。完全相同的变化，氧化应激急性生殖性腺切除术在5个月大的女性或男性和逆转雌激素或雄激素在体内以及体外。我们的结论是，氧化应激的生理有机体老化小鼠可能是一个关键的发病机制与年龄相关的骨丢失和强度。雌激素或雄激素的丢失通过降低对氧化应激的防御来加速衰老对骨骼的影响。
Both aging and loss of sex steroids have adverse effects on skeletal homeostasis, but whether and how they may influence each others negative impact on bone remains unknown. We report herein that both female and male C57BL/6 mice progressively lost strength (as determined by load-to-failure measurements) and bone mineral density in the spine and femur between the ages of 4 and 31 months. These changes were temporally associated with decreased rate of remodeling as evidenced by decreased osteoblast and osteoclast numbers and decreased bone formation rate; as well as increased osteoblast and osteocyte apoptosis, increased reactive oxygen species levels, and decreased glutathione reductase activity and a corresponding increase in the phosphorylation of p53 and p66(shc), two key components of a signaling cascade that are activated by reactive oxygen species and influences apoptosis and lifespan. Exactly the same changes in oxidative stress were acutely reproduced by gonadectomy in 5-month-old females or males and reversed by estrogens or androgens in vivo as well as in vitro. We conclude that the oxidative stress that underlies physiologic organismal aging in mice may be a pivotal pathogenetic mechanism of the age-related bone loss and strength. Loss of estrogens or androgens accelerates the effects of aging on bone by decreasing defense against oxidative stress.