The murine glucagon-like peptide-1 receptor is essential for control of bone resorption

被引:241
作者
Yamada, Chizumi [2 ]
Yamada, Yuichiro [1 ,2 ]
Tsukiyama, Katsushi [2 ,6 ]
Yamada, Kotaro [2 ]
Udagawa, Nobuyuki [4 ]
Takahashi, Naoyuki [5 ]
Tanaka, Kiyoshi
Drucker, Daniel J. [7 ,8 ]
Seino, Yutaka [2 ,9 ]
Inagaki, Nobuya [2 ,3 ]
机构
[1] Akita Univ, Sch Med, Dept Internal Med, Div Endocrinol Diabet & Geriatr Med, Akita 0108543, Japan
[2] Kyoto Univ, Grad Sch Med, Dept Diabet & Clin Nutr, Kyoto 6068507, Japan
[3] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Kyoto 6068507, Japan
[4] Matsumoto Dent Univ, Dept Biochem, Nagano 3990781, Japan
[5] Matsumoto Dent Univ, Inst Oral Sci, Nagano 3990781, Japan
[6] Kyoto Womens Univ, Dept Nutr, Kyoto 6058501, Japan
[7] Univ Toronto, Samuel Lunenfeld Res Inst, Dept Med, Mt Sinai Hosp, Toronto, ON M5G 2C4, Canada
[8] Univ Toronto, Bating & Best Diabet Ctr, Toronto, ON M5G 2C4, Canada
[9] Kansai Elect Power Hosp, Osaka 5530003, Japan
关键词
D O I
10.1210/en.2007-1292
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
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 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.
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收藏
页码:574 / 579
页数:6
相关论文
共 33 条
[11]   Calcitonin deficiency in mice progressively results in high bone turnover [J].
Huebner, Antje K. ;
Schinke, Thorsten ;
Priemel, Matthias ;
Schilling, Sarah ;
Schilling, Arndt F. ;
Emeson, Ronald B. ;
Rueger, Johannes M. ;
Amling, Michael .
JOURNAL OF BONE AND MINERAL RESEARCH, 2006, 21 (12) :1924-1934
[12]   Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy [J].
Kahn, Steven E. ;
Haffner, Steven M. ;
Heise, Mark A. ;
Herman, William H. ;
Holman, Rury R. ;
Jones, Nigel P. ;
Kravitz, Barbara G. ;
Lachin, John M. ;
O'Neill, M. Colleen ;
Zinman, Bernard ;
Viberti, Giancarlo .
NEW ENGLAND JOURNAL OF MEDICINE, 2006, 355 (23) :2427-2443
[13]   Expression of glucagon-like peptide 1 receptor in a murine C cell line: Regulation of calcitonin gene by glucagon-like peptide 1 [J].
Lamari, Y ;
Boissard, C ;
Moukhtar, MS ;
Jullienne, A ;
Rosselin, G ;
Garel, JM .
FEBS LETTERS, 1996, 393 (2-3) :248-252
[14]   A comparison of the skeletal effects of intermittent and continuous administration of calcitonin in ovariectomized rats [J].
Li, M ;
Shen, Y ;
Burton, KW ;
DeLuca, PP ;
Mehta, RC ;
Baumann, BD ;
Wronski, TJ .
BONE, 1996, 18 (04) :375-380
[15]   p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function [J].
Li, XT ;
Udagawa, N ;
Itoh, K ;
Suda, K ;
Murase, Y ;
Nishihara, T ;
Suda, T ;
Takahashi, N .
ENDOCRINOLOGY, 2002, 143 (08) :3105-3113
[16]   Decreased bone mineral density at the distal radius, but not at the lumbar spine or the femoral neck, in Japanese type 2 diabetic patients [J].
Majima, T ;
Komatsu, Y ;
Yamada, T ;
Koike, Y ;
Shigemoto, M ;
Takagi, C ;
Hatanaka, I ;
Nakao, K .
OSTEOPOROSIS INTERNATIONAL, 2005, 16 (08) :907-913
[17]   Effect of salmon calcitonin on experimental osteoporosis induced by ovariectomy and low-calcium diet in the rat [J].
Mochizuki, K ;
Inoue, T .
JOURNAL OF BONE AND MINERAL METABOLISM, 2000, 18 (04) :194-207
[18]   THE EFFECT ON VERTEBRAL BONE MASS AND STRENGTH OF LONG-TERM TREATMENT WITH ANTIRESORPTIVE AGENTS (ESTROGEN AND CALCITONIN), HUMAN PARATHYROID HORMONE-(1-38), AND COMBINATION THERAPY, ASSESSED IN AGED OVARIECTOMIZED RATS [J].
MOSEKILDE, L ;
DANIELSEN, CC ;
GASSER, J .
ENDOCRINOLOGY, 1994, 134 (05) :2126-2134
[19]   BONE HISTOMORPHOMETRY - STANDARDIZATION OF NOMENCLATURE, SYMBOLS, AND UNITS [J].
PARFITT, AM ;
DREZNER, MK ;
GLORIEUX, FH ;
KANIS, JA ;
MALLUCHE, H ;
MEUNIER, PJ ;
OTT, SM ;
RECKER, RR .
JOURNAL OF BONE AND MINERAL RESEARCH, 1987, 2 (06) :595-610
[20]   Bone mineral density and its determinants in diabetes: the Fremantle Diabetes Study [J].
Rakic, V ;
Davis, WA ;
Chubb, SAP ;
Islam, FMA ;
Prince, RL ;
Davis, TME .
DIABETOLOGIA, 2006, 49 (05) :863-871