Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis

Song Yi Han, Na Kyung Lee, Kyung Hee Kim, In Whan Jang, Mijung Yim, Jae Hong Kim, Won Jae Lee, Soo Young Lee

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Regulation of osteoclast differentiation is key to understanding the pathogenesis and to developing treatments for bone diseases such as osteoporosis. To gain insight into the mechanism of the receptor activator of nuclear factor (NF)-κB ligand (RANKL)-specific induction of the osteoclast differentiation program, we took a suppression-subtractive hybridization screening approach to identify genes specifically induced via the RANKL-Rac1 signaling pathway. Among identified targets, we show that RANKL selectively induces cyclooxygenase (COX) 2 expression via Rac1 that results in turn in production of prostaglandin E2 (PGE2) in RAW 264.7 cells. By using transient transfection assays, we found that the -233/ -206 region of the COX-2 promoter gene was critical for RANKL-induced promoter activity. This RANKL-responsive region contained an NF-κB site that, when mutated, completely abolished the induction of NF-κB DMA-binding activity by RANKL. Blockade of COX-2 by celecoxib inhibits differentiation of bone marrow-derived monocyte/macrophage precursor cells (BMMs) into tartrate-resistant acid phosphatase-positive (TRAP+) osteoclastic cells. This inhibition can be rescued by the addition of exogenous PGE2, suggesting that COX-2-dependent PGE2 induction by RANKL in osteoclast precursors is required for osteoclast differentiation.

Original languageEnglish
Pages (from-to)1240-1245
Number of pages6
JournalBlood
Volume106
Issue number4
DOIs
Publication statusPublished - 2005 Aug 15

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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