IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.
IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.
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DOI：
10.1002/jbmr.2689
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Sonntag WE
中科院分区：
文献类型：
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作者：
Ashpole NM;Herron JC;Mitschelen MC;Farley JA;Logan S;Yan H;Ungvari Z;Hodges EL;Csiszar A;Ikeno Y;Humphrey MB;Sonntag WE
晚期衰老与骨折的风险增加有关，特别是在椎骨内，其表现出骨小梁结构的显著减少。衰老也与胰岛素样生长因子（IGF-1）循环水平的降低有关。研究表明，IGF-1的减少会损害健康寿命，而其他人则报告说，IGF-1的损失是有益的，因为它会增加健康寿命和寿命。到目前为止，循环IGF-1的减少对脊椎骨老化的影响还没有得到彻底的研究。在这里，我们描绘的后果循环IGF-1的损失对脊椎骨老化的男性和女性Igff/f小鼠。在小鼠寿命期间的多个特定时间点，IGF-1降低-出生后发育早期（白蛋白-Cre小鼠与Igff/f小鼠杂交），或成年早期，以及使用肝特异性病毒载体（AAV 8-TBG-Cre）的成年晚期。使用microCT和定量骨组织形态计量学分析了27个月大时的椎骨骨结构。与先前的研究一致，雄性和雌性小鼠都表现出与年龄相关的椎骨骨结构减少。在雄性小鼠中，在任何年龄诱导的循环IGF-1的减少都不会减少脊椎骨丢失。有趣的是，女性早期IGF-1的丢失导致椎骨体积分数增加67%，以及连接密度增加和骨小梁数量增加。在生命早期IGF-1缺乏的女性中，骨结构的维持与成骨细胞表面增加和循环中骨保护素/NF κ B受体激活剂-配体水平的比例增加有关。在IGF-1缺失的3个月内，我们的雌性小鼠的椎骨内胰岛素受体表达增加了2.2倍，这表明局部信号传导可能补偿了循环IGF-1的缺失。总之，这些数据表明，女性与年龄相关的椎骨骨密度损失可以通过改变生命早期的循环IGF-1水平来减少。
Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, while others report that loss of IGF-1 is beneficial as it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igff/f mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan- early in postnatal development (crossing albumin-Cre mice with Igff/f mice), or early adulthood, and late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using microCT and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NFkB-ligand levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2 fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data suggest the age-related loss of vertebral bone density in females can be reduced by modifying circulating IGF-1 levels early in life.