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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cells, Cultured
-
Chondrocytes / drug effects
-
Chondrocytes / enzymology
-
Chondrocytes / metabolism*
-
Dimerization
-
Enzyme Activation
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Gene Expression Regulation, Enzymologic
-
Humans
-
Interleukin-1 Receptor-Associated Kinases / genetics
-
Interleukin-1 Receptor-Associated Kinases / metabolism*
-
Interleukin-1beta / metabolism*
-
JNK Mitogen-Activated Protein Kinases / metabolism
-
MAP Kinase Signaling System
-
Matrix Metalloproteinase 13 / genetics
-
Matrix Metalloproteinase 13 / metabolism*
-
Mitogen-Activated Protein Kinases / metabolism*
-
Myeloid Differentiation Factor 88 / antagonists & inhibitors
-
Myeloid Differentiation Factor 88 / genetics
-
Myeloid Differentiation Factor 88 / metabolism*
-
Peptides / pharmacology
-
Phosphorylation
-
Promoter Regions, Genetic* / drug effects
-
Proto-Oncogene Proteins c-jun / metabolism
-
RNA Interference*
-
RNA, Small Interfering / metabolism
-
TNF Receptor-Associated Factor 6 / genetics
-
TNF Receptor-Associated Factor 6 / metabolism*
-
Transcription Factor AP-1 / metabolism
-
Transfection
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
Interleukin-1beta
-
MYD88 protein, human
-
Myeloid Differentiation Factor 88
-
Peptides
-
Proto-Oncogene Proteins c-jun
-
RNA, Small Interfering
-
TNF Receptor-Associated Factor 6
-
Transcription Factor AP-1
-
IRAK1 protein, human
-
Interleukin-1 Receptor-Associated Kinases
-
Extracellular Signal-Regulated MAP Kinases
-
JNK Mitogen-Activated Protein Kinases
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
Matrix Metalloproteinase 13