Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism

Michael L. Major, Herman S. Cheung, Ravi P. Misra

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Diseases caused by calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals occur frequently in osteoarthritic joints. Both crystals induce mitogenesis, metalloproteinase synthesis and secretion by fibroblasts and chondrocytes, promoting degradation of articular tissue. We investigated the mechanism by which BCP activates the c-fos proto-oncogene, which has been shown to activate various matrix metalloproteinases (MMPs). We demonstrate that BCP crystals induce c-fos expression primarily through a Ras/ERK-dependent signaling mechanism targeting two highly conserved regulatory binding sites, the serum response element (SRE) and the cAMP response element (CRE). These results establish a calcium crystal induced, calcium/calmodulin independent, signaling pathway in which BCP crystals activate Ras/MAPK, which can directly target an SRF-containing transcription factor complex, to induce fibroblasts to secrete metalloproteinases.

Original languageEnglish (US)
Pages (from-to)654-660
Number of pages7
JournalBiochemical and biophysical research communications
Volume355
Issue number3
DOIs
StatePublished - Apr 13 2007

Keywords

  • Basic calcium phosphate
  • c-fos
  • CREB
  • Osteoarthritis
  • SRF

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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