The Murine Glucagon-Like Peptide-1 Receptor Is Essential for Control of Bone Resorption

内分泌学 内科学 骨吸收 脱氧吡啶啉 骨重建 破骨细胞 降钙素 吸收 化学 降钙素受体 骨矿物 降钙素基因相关肽 骨质疏松症 受体 医学 骨钙素 神经肽 碱性磷酸酶 生物化学
作者
Chizumi Yamada,Yuichiro Yamada,Katsushi Tsukiyama,Kotaro Yamada,Nobuyuki Udagawa,Naoyuki Takahashi,Kiyoshi Tanaka,Daniel J. Drucker,Yutaka Seino,Nobuya Inagaki
出处
期刊:Endocrinology [Oxford University Press]
卷期号:149 (2): 574-579 被引量:265
标识
DOI:10.1210/en.2007-1292
摘要

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 Glp-1r−/− 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.
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