title: Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18.
abstract: 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 beta-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.
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
authors.forename: Ravi M
authors.initials: RM
authors.lastname: Kapadia
authors.forename: Anyonya R
authors.initials: AR
authors.lastname: Guntur
authors.forename: Martina I
authors.initials: MI
authors.lastname: Reinhold
authors.forename: Michael C
authors.initials: MC
authors.lastname: Naski
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects; D017931:DNA Primers; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008682:Metatarsal Bones / Q000196:embryology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D016133:Polymerase Chain Reaction; D051176:beta Catenin / Q000378:metabolism
chemical_list: D017931:DNA Primers; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D051176:beta Catenin; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D001973:Bromodeoxyuridine