Glucose suppresses IL-1β-induced MMP-1 expression through the FAK, MEK, ERK, and AP-1 signaling pathways

Environ Toxicol. 2018 Oct;33(10):1061-1068. doi: 10.1002/tox.22618. Epub 2018 Aug 11.


Osteoarthritis (OA) commonly affects the synovial joint and is characterized by degradation of articular cartilage. Increased matrix metalloproteinase (MMP) activity plays a major role in this degradation. Dextrose (D-glucose) prolotherapy has shown promising activity in the treatment of different musculoskeletal disorders, including OA. However, little is known about the role of glucose on MMP inhibition in OA therapy. We found that stimulating chondrocytes with the proinflammatory cytokine interleukin-1β (IL-1β) increased the expression of MMP-1, MMP-3, and MMP-13. Glucose reduced this increase in MMP-1 expression, but had no effect upon MMP-3 or MMP-13 expression. Analyses using a focal adhesion kinase (FAK) inhibitor, MEK inhibitors (U0126 and PD98059), an ERK inhibitor, AP-1 inhibitors (curcumin and tanshinone), or siRNAs demonstrated that the FAK, MEK, ERK, and AP-1 pathways mediate IL-1β-induced increases in MMP-1 expression. Glucose antagonized IL-1β-promoted phosphorylation of FAK, MEK, ERK, and c-Jun. Thus, glucose decreased IL-1β-induced MMP-1 expression through the FAK, MEK, ERK, and AP-1 signaling cascades. These findings may provide a better understanding of the mechanisms of prolotherapy on inhibiting MMP expression.

Keywords: IL-1β; MMP-1; chondrocytes; glucose; osteoarthritis.

MeSH terms

  • Animals
  • Cell Line
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Glucose / pharmacology*
  • Interleukin-1beta / pharmacology*
  • Matrix Metalloproteinase 1 / metabolism*
  • Matrix Metalloproteinase 13 / metabolism
  • Matrix Metalloproteinase 3 / metabolism
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism*


  • Interleukin-1beta
  • Transcription Factor AP-1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1
  • Glucose