Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in TallyHo/JngJ mice.
Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in TallyHo/JngJ mice.
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DOI：
10.1371/journal.pone.0018168
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发表时间：
2011-03-25
期刊：
影响因子：
3.7
通讯作者：
Bae MA
中科院分区：
文献类型：
--
作者：
Won HY;Lee JA;Park ZS;Song JS;Kim HY;Jang SM;Yoo SE;Rhee Y;Hwang ES;Bae MA
越来越多的证据表明，骨密度下降和骨折发生率增加与异常代谢状态（如高血糖和胰岛素抵抗）有关，这表明糖尿病是骨质疏松症的一个危险因素。在本研究中，我们观察到2型糖尿病多基因模型TallyHo/ jnj （TH）小鼠自发发生骨质疏松特征的骨畸形。随着年龄的增长，雌性和雄性TH小鼠的体重明显高于对照组C57BL/6小鼠。有趣的是，雄性TH小鼠的骨密度显著降低，表现出高血糖。TH小鼠的成骨细胞特异性骨形成标志物骨钙素和骨保护素降低，而破骨细胞驱动的骨吸收标志物IL-6和RANKL在TH小鼠的骨髓和血液中显著升高。此外，在T细胞受体刺激后，TH小鼠CD4+ T细胞中RANKL的表达显著升高，这与IL-17的产生增强是一致的。瘦素直接促进CD4+ T细胞中IL-17的产生，而IFN-γ的产生则没有作用。此外，阻断IFN-γ进一步增加了TH-CD4+ T细胞中RANKL的表达和IL-17的产生。此外，阿仑膦酸钠可改善TH小鼠的骨质疏松表型。这些结果强烈表明，TH小鼠瘦素升高可能与IL-6联合作用，优先刺激CD4+ T细胞中IL-17的产生，并诱导rankl介导的破骨细胞生成。因此，我们认为TH小鼠可能是骨质疏松症的有益模型。
Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis.
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