Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-κB) transcription factors down-regulates matrix …

A Liacini, J Sylvester, WQ Li, M Zafarullah - Matrix Biology, 2002 - Elsevier
A Liacini, J Sylvester, WQ Li, M Zafarullah
Matrix Biology, 2002Elsevier
Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces
matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The
molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-
activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and
nuclear factor kappa B (NF-κB) transcription factors. IL-1 rapidly induced the activation of
extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase …
Interleukin-1 (IL-1), the main cytokine instigator of cartilage degeneration in arthritis, induces matrix metalloproteinase-3 (MMP-3) and MMP-13 RNA and protein in chondrocytes. The molecular mechanisms of this induction were investigated with specific inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and activating protein (AP-1) and nuclear factor kappa B (NF-κB) transcription factors. IL-1 rapidly induced the activation of extracellular-signal regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK) MAPKs in the first-passage human femoral head OA chondrocytes. The ERK-MAPK pathway inhibitor, PD98059, attained 46–53% (MMP-3) and 59–66% (MMP-13) inhibition of RNA induction in human OA and 47–52% (MMP-3) and 69–73% (MMP-13) inhibition in bovine chondrocytes. U0126 conferred 37–77% (MMP-3) and 43–73% (MMP-13) suppression in human and 77–100% (MMP-3) and 96–100% (MMP-13) in bovine chondrocytes. P38 and JNK inhibitor, SB203580 caused 35–37% reduction of MMP-3 and MMP-13 RNA in human and 36–46% (MMP-3) and 60–88% (MMP-13) in bovine chondrocytes. Inhibitor of JNK, AP-1 and NF-κB, curcumin, achieved 48–99% suppression of MMP-3 and 45–97% of MMP-13 in human and 8–100% (MMP-3) and 32–100% (MMP-13) in bovine chondrocytes. NF-κB inhibitor, pyrrolidine dithiocarbamate yielded 83–84% reduction of MMP-3 and 38–55% for MMP-13 in human chondrocytes. In bovine chondrocytes, the induction decreased by 54–64% for MMP-3 and 74–93% for MMP-13 RNA. These results suggest the involvement of MAPKs, AP-1 and NF-κB transcription factors in the IL-1 induction of MMPs in chondrocytes. Inhibition of IL-1 signal transduction by these agents could be useful for reducing cartilage resorption by MMPs in arthritis.
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