Upstream stimulatory factors regulate OSCAR gene expression in RANKL-mediated osteoclast differentiation

J Mol Biol. 2008 Nov 14;383(3):502-11. doi: 10.1016/j.jmb.2008.08.036. Epub 2008 Aug 22.

Abstract

Receptor activator of nuclear factor kappaB ligand (RANKL) induces osteoclast differentiation from hematopoietic precursors via regulation of various transcription factors. Here, we show that upstream stimulatory factors (USFs), which are basic helix-loop-helix leucine zipper transcription factors, are involved in RANKL-mediated osteoclastogenesis and regulation of osteoclast-associated receptor (OSCAR) gene expression, which is an important costimulatory receptor for osteoclast differentiation. USF-1 and USF-2 are expressed in hematopoietic osteoclast precursors and mature osteoclasts. Interestingly, down-regulation of USF-1 by RNA interference or overexpression of a dominant-negative form of USF-1 attenuates osteoclast formation and expression of OSCAR during osteoclastogenesis. Promoter analysis and chromatin immunoprecipitation assays reveal that USFs bind directly to an E-box site in the OSCAR promoter region and activate OSCAR. In addition, USFs interact and cooperate with nuclear factor of activated T cells c1 in regulating OSCAR gene expression. Taken together, our results indicate that USFs serve as modulators in the induction of OSCAR and RANKL-mediated osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / physiology
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Gene Expression Regulation*
  • Humans
  • MAP Kinase Kinase 6 / genetics
  • MAP Kinase Kinase 6 / metabolism
  • Macrophages / cytology
  • Macrophages / physiology
  • Mice
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / physiology*
  • RANK Ligand / genetics
  • RANK Ligand / metabolism*
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / physiology
  • Upstream Stimulatory Factors / genetics
  • Upstream Stimulatory Factors / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Oscar protein, mouse
  • RANK Ligand
  • Receptors, Cell Surface
  • Upstream Stimulatory Factors
  • Usf1 protein, mouse
  • Usf2 protein, mouse
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 6
  • Map2k6 protein, mouse