EP4 receptor regulates collagen type-I, MMP-1, and MMP-3 gene expression in human tendon fibroblasts in response to IL-1 beta treatment

Gene. 2007 Jan 15;386(1-2):154-61. doi: 10.1016/j.gene.2006.08.027. Epub 2006 Sep 15.


Tendinopathy is accompanied by inflammation, tendon matrix degradation, or both. Inflammatory cytokine IL-1beta, which is a potent inflammatory mediator, is likely present within the tendon. The purpose of this study was to determine the biological impact of IL-1beta on tendon fibroblasts by assessing the expression of cPLA(2), COX-2, PGE(2) and its receptors (EPs), collagen type-I, and MMPs. We also studied the role of the p38 MAPK pathway in IL-1beta-induced catabolic effects. We found that IL-1beta increased the expression levels of cPLA(2) and COX-2, and also increased the secretion of PGE(2). Induction of MMPs, such as MMP-1 and MMP-3 at the mRNA level, was also observed after stimulation with IL-1beta. Furthermore, the presence of IL-1beta significantly decreased the level of collagen type-I mRNA in tendon fibroblasts. These effects were found to be mediated by selective upregulation of EP(4) receptor, which is a member of G-protein-coupled receptor that transduces the PGE(2) signal. Blocking EP(4) receptor by a specific chemical inhibitor abolished IL-1beta-induced catabolic effects. These results suggest that IL-1beta-induced catabolic action on tendon fibroblasts occurs via the upregulation of two key inflammatory mediators, cPLA(2) and COX-2, which are responsible for the synthesis of PGE(2). IL-1beta further stimulates the expression of EP(4) receptor, suggesting positive feedback regulation which may lead to accelerated catabolic processes in tendon fibroblasts. Studies using pathway-specific chemical inhibitors suggest that the p38 MAPK pathway is the key signaling cascade transducing IL-1beta-mediated catabolic effects. Collectively, our findings suggest that the EP(4) receptor mediates the IL-1beta-induced catabolic metabolism via the p38 MAPK pathway in human tendon fibroblasts and may play a major role in the tendon's degenerative changes often seen in the later stages of tendinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Collagen Type I / biosynthesis
  • Collagen Type I / genetics*
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Fibroblasts / metabolism*
  • Gene Expression Regulation / physiology
  • Humans
  • Interleukin-1beta / physiology*
  • MAP Kinase Signaling System / physiology
  • Male
  • Matrix Metalloproteinase 1 / biosynthesis
  • Matrix Metalloproteinase 1 / genetics*
  • Matrix Metalloproteinase 3 / biosynthesis
  • Matrix Metalloproteinase 3 / genetics*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Phospholipases A / biosynthesis
  • Phospholipases A / genetics
  • Receptors, Prostaglandin E / physiology*
  • Receptors, Prostaglandin E, EP4 Subtype
  • Tendons / cytology
  • Tendons / metabolism
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Collagen Type I
  • Interleukin-1beta
  • Membrane Proteins
  • PTGER4 protein, human
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP4 Subtype
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • p38 Mitogen-Activated Protein Kinases
  • Phospholipases A
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1