title: Deletion of glycogen synthase kinase-3β in cartilage results in up-regulation of glycogen synthase kinase-3α protein expression.
abstract: The rate of endochondral bone growth determines final height in humans and is tightly controlled. Glycogen synthase kinase-3 (GSK-3) is a negative regulator of several signaling pathways that govern bone growth, such as insulin/IGF and Wnt/β-catenin. The two GSK-3 proteins, GSK-3α and GSK-3β, display both overlapping and distinct roles in different tissues. Here we show that pharmacological inhibition of GSK-3 signaling in a mouse tibia organ culture system results in enhanced bone growth, accompanied by increased proliferation of growth plate chondrocytes and faster turnover of hypertrophic cartilage to bone. GSK-3 inhibition rescues some, but not all, effects of phosphatidylinositide 3-kinase inhibition in this system, in agreement with the antagonistic role of these two kinases in response to signals such as IGF. However, cartilage-specific deletion of the Gsk3b gene in mice has minimal effects on skeletal growth or development. Molecular analyses demonstrated that compensatory up-regulation of GSK-3α protein levels in cartilage is the likely cause for this lack of effect. To our knowledge, this is the first tissue in which such a compensatory mechanism is described. Thus, our study provides important new insights into both skeletal development and the biology of GSK-3 proteins.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada. fbeier@uwo.ca
authors.forename: J R
authors.initials: JR
authors.lastname: Gillespie
authors.forename: V
authors.initials: V
authors.lastname: Ulici
authors.forename: H
authors.initials: H
authors.lastname: Dupuis
authors.forename: A
authors.initials: A
authors.lastname: Higgs
authors.forename: A
authors.initials: A
authors.lastname: Dimattia
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: J R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: F
authors.initials: F
authors.lastname: Beier
mesh_terms: D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002356:Cartilage / Q000201:enzymology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006132:Growth Plate / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013977:Tibia / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha