Urokinase plasminogen activator system in synovial fibroblasts from osteoarthritis patients: modulation by inflammatory mediators and neuropeptides

J Mol Neurosci. 2014 Jan;52(1):18-27. doi: 10.1007/s12031-013-0189-z. Epub 2013 Dec 7.


Plasminogen activators are specific proteolytic enzymes implicated in a variety of basic biological processes. The expression of the urokinase plasminogen activator system components is increased in some human diseases, including osteoarthritis. We sought to study the effect of two components of the inflamed synovial microenvironment on this system, IL-1β and fibronectin fragments, elucidating whether corticotropin-releasing factor (CRF) and vasoactive intestinal peptide (VIP) neuropeptides modulate it, and analyzing the physiological consequences in joint destruction by measuring matrix metalloproteinases-9 and metalloproteinases-13 levels in osteoarthritis fibroblast-like synoviocytes. We showed that IL-1β and fibronectin fragments stimulated urokinase system contributing to the perpetuation of the destructive cascade in joint. VIP modulated, even at constitutive level, this system, also counteracting the effect of both inflammatory stimuli. However, CRF seemed to be ineffective in controlling the production of these proteinases. Moreover, VIP was able to reduce the constitutive expression of matrix metalloproteinase-13 and the levels of both matrix metalloproteinases after stimulation with the pro-inflammatory stimuli. Our results suggest that the presence of early and later inflammatory mediators, such as IL-1β and fibronectin fragments, increases the urokinase system and the matrix metalloproteinases levels. Whereas CRF did not affect this system, VIP counteracts these actions supporting its therapeutic potential for the treatment of osteoarthritis.

Publication types

  • Historical Article
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Corticotropin-Releasing Hormone / pharmacology*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibronectins / pharmacology
  • History, 18th Century
  • Humans
  • Inflammation Mediators / pharmacology*
  • Interleukin-1beta / pharmacology
  • Joint Capsule / metabolism
  • Joint Capsule / pathology
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Osteoarthritis / metabolism*
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism*
  • Vasoactive Intestinal Peptide / pharmacology*


  • Fibronectins
  • Inflammation Mediators
  • Interleukin-1beta
  • Vasoactive Intestinal Peptide
  • Corticotropin-Releasing Hormone
  • Urokinase-Type Plasminogen Activator
  • MMP13 protein, human
  • Matrix Metalloproteinase 13