Fibroblast growth factor 2 and cyclic AMP synergistically regulate bone sialoprotein gene expression

Emi Shimizu, Youhei Nakayama, Yu Nakajima, Naoko Kato, Hideki Takai, Dong Soon Kim, Masato Arai, Ryoichiro Saito, Jaro Sodek, Yorimasa Ogata

Research output: Contribution to journalArticlepeer-review

Abstract

Bone sialoprotein (BSP) is a noncollagenous protein of the mineralized bone extracellular matrix. We here report that FGF2 and cAMP act synergistically to stimulate BSP gene expression. Treatment of ROS 17/2.8 cells with either 10 ng/ml FGF2 or 1 μM FSK for 6 h resulted in 5.4- and 8.2-fold increases, respectively, in the levels of BSP mRNA. However, in the presence of both FGF2 and forskolin (FGF/FSK), BSP mRNA levels were increased synergistically by 20.4-fold. Using a luciferase reporter construct, encompassing BSP promoter nucleotides -116 to +60, transcription was also increased synergistically by 15.0-fold with FGF/FSK, compared to stimulations of 2.6- and 5.3-fold, respectively, for FGF2 and FSK alone. Transcriptional stimulation by FGF/FSK abrogated in constructs included 2 bp mutations in the inverted CCAAT, CRE, FRE and Pit-1 elements. Whereas the FRE-protein complex was increased by FGF2 and FGF/FSK, the Pit-1-protein complex was decreased by FSK and FGF/FSK. Notably, transcriptional activity induced by FGF/FSK was blocked by protein kinase A, tyrosine kinase and MEK inhibitors. These studies indicate that the combinatorial effects of FGF and FSK act through PKA, tyrosine kinase and MAP-kinase-dependent pathways, which target the inverted CCAAT, CRE, FRE and Pit-1 elements in the BSP gene to synergistically increase BSP expression.

Original languageEnglish (US)
Pages (from-to)42-52
Number of pages11
JournalBone
Volume39
Issue number1
DOIs
StatePublished - Jul 2006

Keywords

  • Basic fibroblast growth factor
  • Bone sialoprotein
  • Gene expression
  • cAMP

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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