Glycogen synthase kinase 3 controls endochondral bone development: Contribution of fibroblast growth factor 18

• Published in: Developmental biology Vol. 285; no. 2; pp. 496 - 507
• Main Authors: Kapadia, Ravi M., Guntur, Anyonya R., Reinhold, Martina I., Naski, Michael C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2005
• Subjects: Animals; beta Catenin - metabolism; Bone; Bromodeoxyuridine; Cartilage; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Chondrocyte; Chondrocytes - cytology; Chondrocytes - drug effects; DNA Primers; FGF18; Fibroblast Growth Factors - metabolism; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - physiology; Glycogen synthase kinase; Glycogen Synthase Kinase 3 - antagonists & inhibitors; In Situ Hybridization; Indoles - pharmacology; Lithium - pharmacology; Maleimides - pharmacology; Metatarsal Bones - embryology; Mice; Osteoblasts - cytology; Osteoblasts - drug effects; Polymerase Chain Reaction; β-catenin; Cartilage; β-catenin; Bone; Chondrocyte; Glycogen synthase kinase; FGF18
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2005.07.029

Glycogen synthase kinase 3 (GSK3) inhibits signaling pathways that are essential for bone development. To study the requirement for GSK activity during endochondral bone development, we inhibited GSK3 in cultured metatarsal bones with pharmacological antagonists. Interestingly, we find that inhibition of GSK3 strongly repressed chondrocyte and perichondrial osteoblast differentiation. Moreover, chondrocyte proliferation was inhibited, whereas perichondrial cell proliferation was stimulated. These results mirror the effects of fibroblast growth factor signaling (FGF), suggesting the FGF expression is induced. Indeed, we showed that (1) FGF18 expression is stimulated following inhibition of GSK3 and (2) GSK3 regulates FGF18 expression through the control of β-catenin levels. Stimulation of cultured metatarsal with FGF18 had similar effects on the differentiation and proliferation of chondrocytes and perichondrial cells as GSK3 repression. This suggests that the regulation of FGF18 expression is a major function of GSK3 during endochondral bone development. Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3.