Article Text

Download PDFPDF
Extended report
Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma?
  1. Mirko Manetti1,
  2. Irene Rosa1,
  3. Anna Franca Milia1,
  4. Serena Guiducci2,
  5. Peter Carmeliet3,4,
  6. Lidia Ibba-Manneschi1,
  7. Marco Matucci-Cerinic2
  1. 1Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy
  2. 2Department of Experimental and Clinical Medicine, Section of Internal Medicine and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
  3. 3Laboratory of Angiogenesis and the Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium
  4. 4Laboratory of Angiogenesis and the Neurovascular Link, Vesalius Research Center, University of Leuven, Leuven, Belgium
  1. Correspondence to Dr Mirko Manetti, Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 3, Florence I-50134, Italy; mirkomanetti{at}, mirko.manetti{at}


Objective Urokinase-type plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodelling and angiogenesis. The cleavage/inactivation of uPAR is a crucial step in fibroblast-to-myofibroblast transition and has been implicated in systemic sclerosis (SSc) microvasculopathy. In the present study, we investigated whether uPAR gene inactivation in mice could result in tissue fibrosis and peripheral microvasculopathy resembling human SSc.

Methods The expression of the native full-length form of uPAR in human skin biopsies was determined by immunohistochemistry. Skin and lung sections from uPAR-deficient (uPAR−/−) and wild-type (uPAR+/+) mice at 12 and 24 weeks of age were stained with haematoxylin-eosin, Masson's trichrome and Picrosirius red. Dermal thickness and hydroxyproline content in skin and lungs were quantified. Dermal myofibroblast and microvessel counts were determined by immunohistochemistry for α-smooth muscle actin and CD31, respectively. Endothelial cell apoptosis was assessed by TUNEL/CD31 immunofluorescence assay.

Results Full-length uPAR expression was significantly downregulated in SSc dermis, especially in fibroblasts and endothelial cells. Dermal thickness, collagen content and myofibroblast counts were significantly greater in uPAR−/− than in uPAR+/+ mice. In uPAR−/− mice, dermal fibrosis was paralleled by endothelial cell apoptosis and severe loss of microvessels. Lungs from uPAR−/− mice displayed non-specific interstitial pneumonia-like pathological features, both with inflammation and collagen deposition. Pulmonary pathology worsened significantly from 12 to 24 weeks, as shown by a significant increase in alveolar septal width and collagen content.

Conclusions uPAR−/− mice are a new animal model closely mimicking the histopathological features of SSc. This model warrants future studies.

  • Systemic Sclerosis
  • Pulmonary Fibrosis
  • Qualitative research

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.