title: Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology.
abstract: OBJECTIVE
  Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis.
  
  
  METHODS
  OA was induced in wild-type (WT) and PAR2-deficient (PAR2-/-) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2-/-mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain.
  
  
  RESULTS
  Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2-/-mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2-/-mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2-/-mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone.
  
  
  CONCLUSIONS
  This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes.
authors.affiliation: Institute of Biomedical & Environmental Health Research, University of the West of Scotland, Paisley, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Huesa
authors.affiliation: Institute of Biomedical & Environmental Health Research, University of the West of Scotland, Paisley, UK.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Ortiz
authors.affiliation: Institute of Biomedical & Environmental Health Research, University of the West of Scotland, Paisley, UK.
authors.forename: Lynette
authors.initials: L
authors.lastname: Dunning
authors.affiliation: Institute of Biomedical & Environmental Health Research, University of the West of Scotland, Paisley, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: McGavin
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Bennett
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: McIntosh
authors.affiliation: Institute of Biomedical & Environmental Health Research, University of the West of Scotland, Paisley, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Crilly
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Mariola
authors.initials: M
authors.lastname: Kurowska-Stolarska
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
authors.affiliation: Institute of Ageing and Chronic Diseases, University of Liverpool, Liverpool, UK.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: van 't Hof
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Carl S
authors.initials: CS
authors.lastname: Goodyear
authors.affiliation: Institute of Biomedical & Environmental Health Research, University of the West of Scotland, Paisley, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.affiliation: Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
mesh_terms: D000818:Animals; D018771:Arthralgia / Q000209:etiology / Q000473:pathology; D001169:Arthritis, Experimental / Q000209:etiology / Q000473:pathology*; D001842:Bone and Bones / Q000473:pathology*; D002358:Cartilage, Articular / Q000473:pathology*; D019902:Chondrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D010003:Osteoarthritis / Q000209:etiology / Q000473:pathology*; D010011:Osteocytes / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*
chemical_list: D044464:Receptor, PAR-2
keywords: Chondrocytes; Inflammation; Osteoarthritis; Synovitis