The murine glucagon-like peptide-1 receptor is essential for control of bone resorption
The murine glucagon-like peptide-1 receptor is essential for control of bone resorption
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DOI：
10.1210/en.2007-1292
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发表时间：
2008-02-01
期刊：
影响因子：
4.8
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
--
作者：
Yamada, Chizumi;Yamada, Yuichiro;Inagaki, Nobuya
胃肠激素包括胃抑制多肽(GIP)、胰高血糖素样肽(GLP)-1和GLP-2，在进食后立即分泌，GIP和GLP-2已被证明对骨转换有调节作用。我们假设内源性GLP-1可能对控制骨骼内环境平衡也很重要。我们利用GLP-1受体基因敲除(GLP-1R(-/-))小鼠研究了GLP-1在骨代谢调节中的作用。结合骨密度和组织形态计量学、破骨细胞活化研究、钙和甲状旁腺素的生化分析以及RNA分析来表征GLP1R(-/-)和GLP-1R(-/-)对照的骨和矿物质的动态平衡。骨密度计量学显示GLP-1R(-)/(-)小鼠皮质骨量减少，骨脆性增加，骨组织形态计量学显示破骨细胞数量增加，骨吸收活性增强。尽管GLP-1对破骨细胞和成骨细胞没有直接影响，但GLP-1R(-/-)小鼠的尿脱氧吡啶(骨吸收的标志)水平较高，而甲状腺中降钙素mRNA转录水平较低。此外，降钙素治疗有效地抑制了GLP-1R(-/-)小鼠的尿脱氧吡啶水平，GLP-1受体激动剂exendin-4增加了野生型小鼠甲状腺中降钙素基因的表达。这些发现确立了内源性GLP-1受体信号在骨吸收控制中的重要作用，可能是通过降钙素依赖的途径。
Gastrointestinal hormones including gastric inhibitory polypeptide ( GIP), glucagon-like peptide (GLP)-1, and GLP-2 are secreted immediately after meal ingestion, and GIP and GLP-2 have been shown to regulate bone turnover. We hypothesize that endogenous GLP-1 may also be important for control of skeletal homeostasis. We investigated the role of GLP-1 in the regulation of bone metabolism using GLP-1 receptor knockout (Glp-1r(-/-)) mice. A combination of bone density and histomorphometry, osteoclast activation studies, biochemical analysis of calcium and PTH, and RNA analysis was used to characterize bone and mineral homeostasis in Glp1r(-/-) and Glp-1r(-/-) littermate controls. Glp-1r(-)/(-) mice have cortical osteopenia and bone fragility by bone densitometry as well as increased osteoclastic numbers and bone resorption activity by bone histomorphometry. Although GLP-1 had no direct effect on osteoclasts and osteoblasts, Glp-1r(-/-) mice exhibited higher levels of urinary deoxypyridinoline, a marker of bone resorption, and reduced levels of calcitonin mRNA transcripts in the thyroid. Moreover, calcitonin treatment effectively suppressed urinary levels of deoxypyridinoline in Glp-1r(-/-), mice and the GLP-1 receptor agonist exendin-4 increased calcitonin gene expression in the thyroid of wild-type mice. These findings establish an essential role for endogenous GLP-1 receptor signaling in the control of bone resorption, likely through a calcitonin-dependent pathway.