High molecular weight hyaluronic acid inhibits IL-6-induced MMP production from human chondrocytes by up-regulating the ERK inhibitor, MKP-1

Biochem Biophys Res Commun. 2010 Dec 10;403(2):184-9. doi: 10.1016/j.bbrc.2010.10.135. Epub 2010 Nov 6.


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.

MeSH terms

  • Cells, Cultured
  • Chondrocytes / drug effects*
  • Chondrocytes / enzymology
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Humans
  • Hyaluronic Acid / pharmacology*
  • Interleukin-6 / pharmacology*
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / biosynthesis
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • RNA, Small Interfering / genetics


  • Interleukin-6
  • Matrix Metalloproteinase Inhibitors
  • RNA, Small Interfering
  • Hyaluronic Acid
  • Extracellular Signal-Regulated MAP Kinases
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Dual Specificity Phosphatase 1
  • Matrix Metalloproteinases