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

Department of Diabetes and Clinical Nutrition (C.Y., Y.Y., K.T., K.Y., Y.S., N.I.), Kyoto University Graduate School of Medicine, and Core Research for Evolutional Science and Technology of Japan Science and Technology Cooperation (N.I), Kyoto 606-8507, Japan; Department of Internal Medicine (Y.Y.), Division of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, Akita 010-8543, Japan; Department of Biochemistry (N.U.) and Institute for Oral Science (N.T.), Matsumoto Dental University, Nagano 399-0781, Japan; Department of Nutrition (K.T.), Kyoto Women’s University, Kyoto 605-8501, Japan; The Samuel Lunenfeld Research Institute (D.J.D.), Department of Medicine, Mount Sinai Hospital and the Banting and Best Diabetes Center, University of Toronto, Toronto, Canada M5G 2C4; Kansai Electric Power Hospital (Y.S.), Osaka 553-0003, Japan

Address all correspondence and requests for reprints to: Yuichiro Yamada, M.D., Ph.D., Department of Internal Medicine, Division of Endocrinology, Diabetes, and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan. E-mail: yamada{at}gipc.akita-u.ac.jp.

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.