Deletion of glycogen synthase kinase-3β in cartilage results in up-regulation of glycogen synthase kinase-3α protein expression

Endocrinology. 2011 May;152(5):1755-66. doi: 10.1210/en.2010-1412. Epub 2011 Feb 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / pharmacology
  • Animals
  • Blotting, Western
  • Cartilage / enzymology*
  • Cartilage / metabolism
  • Cell Proliferation / drug effects
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Female
  • Gene Deletion
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Growth Plate / drug effects
  • Growth Plate / growth & development
  • Growth Plate / metabolism
  • Immunohistochemistry
  • Male
  • Maleimides / pharmacology
  • Mice
  • Mice, Knockout
  • Organ Culture Techniques
  • Phosphatidylinositol 3-Kinases / metabolism
  • Tibia / drug effects
  • Tibia / enzymology*
  • Tibia / growth & development
  • Up-Regulation
  • beta Catenin / metabolism


  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • Maleimides
  • beta Catenin
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha