title: Co-ordination of TGF-beta and FGF signaling pathways in bone organ cultures.
abstract: Transforming growth factor-beta (TGF-beta) is known to regulate chondrocyte proliferation and hypertrophic differentiation in embryonic bone cultures by a perichondrium dependent mechanism. To begin to determine which factors in the perichondrium mediate the effects of TGF-beta, we studied the effect of Insulin-like Growth Factor-1 (IGF-I) and Fibroblast Growth Factors-2 and -18 (FGF2, FGF18) on metatarsal organ cultures. An increase in chondrocyte proliferation and hypertrophic differentiation was observed after treatment with IGF-I. A similar effect was seen after the perichondrium was stripped from the metatarsals suggesting IGF-I acts directly on the chondrocytes. Treatment with FGF-2 or FGF-18 resulted in a decrease in bone elongation as well as hypertrophic differentiation. Treatment also resulted in a decrease in BrdU incorporation into chondrocytes and an increase in BrdU incorporation in perichondrial cells, similar to what is seen after treatment with TGF-beta1. A similar effect was seen with FGF2 after the perichondrium was stripped suggesting that, unlike TGF-beta, FGF2 acts directly on chondrocytes to regulate proliferation and hypertrophic differentiation. To test the hypothesis that TGF-beta regulates IGF or FGF signaling, activation of the receptors was characterized after treatment with TGF-beta. Activation was measured as the level of tyrosine phosphorylation on the receptor. Treatment with TGF-beta for 24h did not alter the level of IGFR-I tyrosine phosphorylation. In contrast, treatment with TGF-beta resulted in and increase in tyrosine phosphorylation on FGFR3 without alterations in total FGFR3 levels. TGF-beta also stimulated expression of FGF18 mRNA in the cultures and the effects of TGF-beta on metatarsal development were blocked or partially blocked by pretreatment with FGF signaling inhibitors. The results suggest a model in which FGF through FGFR3 mediates some of the effects of TGF-beta on embryonic bone formation.
authors.affiliation: Department of Pathology, University of Alabama, Birmingham, AL 35294-0005, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Sai Sai
authors.initials: SS
authors.lastname: Dong
authors.forename: Thomas
authors.initials: T
authors.lastname: Clemens
authors.forename: Jesus
authors.initials: J
authors.lastname: Alvarez
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006614:Hindlimb / Q000166:cytology / Q000196:embryology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008682:Metatarsal Bones / Q000166:cytology* / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009924:Organ Culture Techniques; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D016212:Transforming Growth Factor beta; C113569:fibroblast growth factor 18; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I