title: Silencing of protease-activated receptors attenuates synovitis and cartilage damage following a joint bleed in haemophilic mice.
abstract: OBJECTIVE
  Joint bleeding results in blood-induced arthropathy. We investigate whether a joint bleed alters protease-activated receptor (PAR) expression, and whether treatment with small interfering RNA (siRNA) targeted against PAR1-4 attenuates synovitis and cartilage damage.
  
  
  METHODS
  Protease-activated receptor expression was evaluated upon a joint bleed in haemophilic mice and in humans. In addition, mice with a joint bleed were randomized between treatment with PAR1-4 siRNA or control and evaluated for the presence of synovitis and cartilage damage. Also, human cartilage was transfected with PAR1-4 siRNA or control, and evaluated for plasmin-induced cartilage damage.
  
  
  RESULTS
  Following a joint bleed, we observed an increase in synovial PAR1, -2 and -4 expression, and an increase in chondrocyte PAR2 and -3 expression in mice (all P < 0.05). Also an increase in synovial PAR1 and chondrocyte PAR4 expression in patients was observed (both P < 0.05). Treatment of a joint bleed in haemophilic mice with PAR1-4 siRNA attenuates synovitis and cartilage damage (both P < 0.01). Treatment of human cartilage tissue explants with PAR1-4 siRNA reduced plasmin-induced cartilage damage (P < 0.01).
  
  
  CONCLUSIONS
  This study demonstrates that synovial and chondrocyte PAR expression is altered upon a joint bleed, and that treatment with PAR1-4 siRNA attenuates synovitis and plasmin-induced cartilage damage.
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands.|Hematology and Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Nieuwenhuizen
authors.affiliation: Hematology and Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands.
authors.forename: R E G
authors.initials: RE
authors.lastname: Schutgens
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Coeleveld
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Mastbergen
authors.affiliation: Clinical Chemistry and Hematology, University Medical Center, Utrecht, The Netherlands.
authors.forename: R M
authors.initials: RM
authors.lastname: Schiffelers
authors.affiliation: Hematology and Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Roosendaal
authors.affiliation: Hematology and Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands.|Internal Medicine, Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands.
authors.forename: D H
authors.initials: DH
authors.lastname: Biesma
authors.affiliation: Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands.
authors.forename: F P J G
authors.initials: FP
authors.lastname: Lafeber
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D005341:Fibrinolysin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006467:Hemophilia A / Q000150:complications*; D006470:Hemorrhage / Q000150:complications* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D044462:Receptors, Proteinase-Activated / Q000172:deficiency* / Q000235:genetics*; D013585:Synovitis / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D034741:RNA, Small Interfering; D044462:Receptors, Proteinase-Activated; D005341:Fibrinolysin
keywords: blood-induced arthropathy; cartilage damage; haemophilia; small interfering RNA; synovitis