Insulin-like growth factor-binding protein-5 induces a gender-related decrease in bone mineral density in transgenic mice
Insulin-like growth factor-binding protein-5 induces a gender-related decrease in bone mineral density in transgenic mice
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DOI：
10.1210/en.2004-0816
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发表时间：
2005-02-01
期刊：
影响因子：
4.8
通讯作者：
Pell, JM
中科院分区：
文献类型：
--
作者：
Salih, DAM;Mohan, S;Pell, JM
在正常骨骼发育过程中，IGF 结合蛋白 5 (IGFBP-5) 在血清和骨骼中含量丰富，但在骨质疏松症中水平会降低。研究表明，IGFBP-5 通过增强 IGF 作用和 IGF 独立作用来刺激骨形成标志物。为了检验 IGFBP-5 促进骨矿物质密度 (BMD) 获得的假设，我们使用巨细胞病毒增强子和 β-肌动蛋白启动子 (CMV/betaA) 生成了过度表达 Igfbp5 的转基因 (Tg) 小鼠。 Tg 动物在 3-8 周龄时血清 IGFBP-5 浓度分别增加了 7.7 至 3.5 倍。在野生型和 Tg 小鼠中，雄性小鼠的浓度比雌性小鼠高 6-49%。令人惊讶的是，BMD 以性别依赖性方式下降，Tg 雄性成年小鼠比 Tg 雌性小鼠受到的影响更严重（通过双能 X 射线吸收测定法评估，与野生型小鼠相比，分别降低 31.3% 和 19.2%）。通过外周定量计算机断层扫描证实了 BMD 的显着性别差异。组织形态计量学显示，尽管 Tg 小鼠骨膜处的骨形成率和矿化表面减少，但骨内膜处的骨形成率和矿化表面增加，表明 IGFBP-5 对骨膜和骨内膜成骨细胞具有相反的作用（通过改变增殖或存活）。这些发现与之前在 Igf1 和 Igf2 缺失动物中的观察结果不同。总之，IGFBP-5 对 BMD 的获得和维持具有显着影响，且影响取决于性别和年龄。 Igfbp5 小鼠的表型不能仅用 IGF 抑制来解释；因此，这项研究通过基因操作，为 IGFBP-5 在骨功能中的不依赖于 IGF 的作用提供了第一个体内证据。这些发现对骨质疏松症的性别偏见进展具有影响。
IGF-binding protein-5 (IGFBP-5) is abundant in serum and bone during normal skeletal development, but levels decrease in osteoporosis. Studies have shown that IGFBP-5 stimulates markers of bone formation by potentiating IGF actions and by IGF-independent actions. To test the hypothesis that IGFBP-5 promotes the acquisition of bone mineral density (BMD), we generated transgenic (Tg) mice overexpressing Igfbp5 using a cytomegalovirus enhancer and beta-actin promoter (CMV/betaA). Tg animals showed an increase in serum IGFBP-5 concentrations by 7.7- to 3.5-fold at 3-8 wk of age, respectively. Concentrations were 6-49% higher for males compared with females in both wild-type and Tg mice. Surprisingly, BMD decreased in a gender-dependent manner, with Tg male adults affected more severely than Tg females (31.3% vs. 19.2% reduction, respectively, compared with wild-type mice, assessed by dual energy x-ray absorptiometry). Significant gender differences in BMD were confirmed by peripheral quantitative computed tomography. Histomorphometry revealed that although the bone formation rate and mineralizing surface at the periosteum decreased in Tg mice, they increased at the endosteum, suggesting opposing effects of IGFBP-5 on periosteal and endosteal osteoblasts (by altering proliferation or survival). These findings differ from previous observations in Igf1- and Igf2-null animals. In conclusion, IGFBP-5 has a significant influence on BMD acquisition and maintenance that is dependent on gender and age. The phenotype of Igfbp5 mice cannot be explained solely by IGF inhibition; thus, this study provides the first in vivo evidence, by genetic manipulation, for IGF-independent actions of IGFBP-5 in bone function. These findings have implications for the gender-biased progression of osteoporosis.