title: GSK-3β function in bone regulates skeletal development, whole-body metabolism, and male life span.
abstract: Glycogen synthase kinase 3 β (GSK-3β) is an essential negative regulator or "brake" on many anabolic-signaling pathways including Wnt and insulin. Global deletion of GSK-3β results in perinatal lethality and various skeletal defects. The goal of our research was to determine GSK-3β cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6-kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b knockout) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3β in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died after weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type 2 diabetes. Our data suggest that skeletal-specific deletion of GSK-3β affects global metabolism and sensitizes male mice to developing type 2 diabetes.
authors.affiliation: Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, Canada; N6A 5C1. fbeier@uwo.ca.
authors.forename: J R
authors.initials: JR
authors.lastname: Gillespie
authors.forename: J R
authors.initials: JR
authors.lastname: Bush
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: L A
authors.initials: LA
authors.lastname: Aubrey
authors.forename: H
authors.initials: H
authors.lastname: Dupuis
authors.forename: M
authors.initials: M
authors.lastname: Ferron
authors.forename: B
authors.initials: B
authors.lastname: Kream
authors.forename: G
authors.initials: G
authors.lastname: DiMattia
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: J R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: G
authors.initials: G
authors.lastname: Karsenty
authors.forename: D A
authors.initials: DA
authors.lastname: Hess
authors.forename: F
authors.initials: F
authors.lastname: Beier
mesh_terms: D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004198:Disease Susceptibility; D004734:Energy Metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007333:Insulin Resistance; D008297:Male; D052801:Male Urogenital Diseases / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012727:Sex Characteristics; D016019:Survival Analysis; D014566:Urogenital System / Q000473:pathology; D014886:Weaning
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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