High molecular weight hyaluronic acid inhibits IL-6-induced MMP production from human chondrocytes by up-regulating the ERK inhibitor, MKP-1.
To investigate the mechanism of the inhibitory action of high molecular weight hyaluronic acid (HA) on production of matrix metalloproteinases (MMPs) induced by IL-6 in human chondrocyte. Human chondrocyte were stimulated by interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) with or without HA for 24h and the productions of MMP-1, MMP-3 and MMP-13 were measured. Phosphorylations of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase kinase (MEK) in IL-6+sIL-6R-treated chondrocytes were detected by western blotting. IL-6+sIL-6R induced MMP-1, MMP-3 and MMP-13 productions from human chondrocyte. Inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway resulted in marked decreases of MMP-1, MMP-3 and MMP-13 induction by IL-6. In contrast, STAT inhibition only slightly attenuated the production of MMPs. HA inhibited MMP-1, MMP-3 and MMP-13 induction by IL-6, which was reversed by the addition of anti-CD44 antibody but not anti-ICAM-1 antibody. Pre-treatment of cells with HA reduced the phosphorylation of ERK, but not MEK. Expression levels of mitogen-activated protein kinase phosphatase-1 (MKP-1) in HA-treated chondrocytes were assessed by western blotting. HA induced the expression of MKP-1, a negative regulator of ERK1/2 in IL-6+sIL-6R-treated or untreated chondrocytes, and the MKP-1 inhibitor and MKP-1 siRNA reversed the HA-induced suppression of MMP induction by IL-6. Our study is the first to demonstrate that HA suppressed MMPs induction by IL-6 in human chondrocyte via MKP-1 induction through CD44 signaling.
Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
Misato
M
Hashizume
Masahiko
M
Mihara
D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D015850:Interleukin-6; D061965:Matrix Metalloproteinase Inhibitors; D034741:RNA, Small Interfering; D006820:Hyaluronic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1; D020782:Matrix Metalloproteinases