MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation

Rasheed Ahmad, Judith Sylvester, Muhammad Zafarullah

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Interleukin-1 (IL-1) is the major prototypic proinflammatory cytokine that stimulates degradation of cartilage in arthritis by inducing prominent collagen II-degrading matrix metalloproteinase-13 (MMP-13). Nothing is known about the involvement of adaptor proteins, MyD88, IRAK1 and TRAF6 in MMP-13 regulation. Here we investigated for the first time the role of these proteins in IL-1-regulated MMP-13 expression in chondrocytes. MyD88 homodimerization inhibitory peptide diminished the expression of MMP-13 gene, promoter activity, phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun and activating protein 1 (AP-1) activity. Knockdown of MyD88, IRAK1 and TRAF6 by RNA interference (RNAi) drastically down-regulated the expression of IL-1-induced MMP-13 mRNA and protein levels and MMP-13 promoter-driven luciferase activity. Non-specific control siRNA had no effect. Mechanisms of MMP-13 inhibition involved reduced phosphorylation of ERK, p38, JNK and c-Jun as well as AP-1 transcription factor binding activity. The genetic evidence presented here demonstrates that MyD88, IRAK1 and TRAF6 proteins are crucial early mediators for the IL-1-induced MMP-13 regulation through MAPK pathways and AP-1 activity. These proteins could constitute important therapeutic targets for arthritis-associated cartilage loss by MMP-13.

Original languageEnglish
Pages (from-to)2549-2557
Number of pages9
JournalCellular Signalling
Volume19
Issue number12
DOIs
Publication statusPublished - 1 Dec 2007

Keywords

  • Cartilage
  • Gene regulation
  • Interleukin-1
  • IRAK1
  • Matrix metalloproteinase-13
  • MyD88
  • Rheumatoid arthritis
  • RNA interference
  • Signal transduction
  • TRAF6
  • Transcription factors

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