The murine glucagon-like peptide-1 receptor is essential for control of bone resorption.
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.
Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Chizumi
C
Yamada
Yuichiro
Y
Yamada
Katsushi
K
Tsukiyama
Kotaro
K
Yamada
Nobuyuki
N
Udagawa
Naoyuki
N
Takahashi
Kiyoshi
K
Tanaka
Daniel J
DJ
Drucker
Yutaka
Y
Seino
Nobuya
N
Inagaki
D015502:Absorptiometry, Photon; D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D002116:Calcitonin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013977:Tibia / Q000000981:diagnostic imaging / Q000502:physiology; D014688:Venoms / Q000378:metabolism / Q000494:pharmacology
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D002116:Calcitonin; D000077270:Exenatide; D002118:Calcium