Erk pathway and activator protein 1 play crucial roles in FGF2-stimulated premature cranial suture closure

Dev Dyn. 2003 Jul;227(3):335-46. doi: 10.1002/dvdy.10319.


Cranial sutures are an important growth center of the cranial bones, and the suture space must be maintained to permit the cranial adjustments needed to accommodate brain growth. Craniosynostosis, characterized by premature suture closure, mainly results from mutations that generate constitutively active fibroblast growth factor (FGF) receptors. FGF signaling, thus, is responsible for the pathogenesis of craniosynostosis. Even though FGF activates many different signaling pathways, the one involved in premature suture closure has not been defined. We observed that placing FGF2-soaked bead on the osteogenic fronts of cultured mouse calvaria accelerates cranial suture closure and strongly induces the expression of osteopontin, an early marker of differentiated osteoblasts. FGF2 treatment also induced fos and jun mRNAs and later increased the nuclear levels of activator protein 1 (AP1). FGF2 stimulates the expression of osteopontin by inducing expression of AP1, which then binds to its response element in the osteopontin promoter. Blocking of the Erk pathway by PD98059 suppressed the AP1 and osteopontin expression stimulated by FGF2. Coincidently, blocking of the Erk pathway also significantly retarded FGF2-accelerated cranial suture closure. Thus, the Erk pathway mediates FGF/FGF receptor-stimulated cranial suture closure, probably by stimulating synthesis of AP1 that then stimulates the differentiation of osteoblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Coloring Agents / pharmacology
  • Craniosynostoses / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Fibroblast Growth Factor 2 / metabolism*
  • Flavonoids / pharmacology
  • Humans
  • In Situ Hybridization
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Oligonucleotides, Antisense / pharmacology
  • Osteoblasts / metabolism
  • Osteopontin
  • Promoter Regions, Genetic
  • RNA / metabolism
  • RNA, Messenger / metabolism
  • Sialoglycoproteins / metabolism
  • Signal Transduction
  • Tetrazolium Salts / pharmacology
  • Thiazoles / pharmacology
  • Time Factors
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor AP-1 / physiology*


  • Coloring Agents
  • Enzyme Inhibitors
  • Flavonoids
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • SPP1 protein, human
  • Sialoglycoproteins
  • Spp1 protein, mouse
  • Tetrazolium Salts
  • Thiazoles
  • Transcription Factor AP-1
  • Fibroblast Growth Factor 2
  • Osteopontin
  • RNA
  • Mitogen-Activated Protein Kinases
  • thiazolyl blue
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one