title: Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3.
abstract: OBJECTIVE
  To explore the involvement of synovial macrophages in early cartilage damage in osteoarthritis (OA), and to identify the role of matrix metalloproteinase 3 (MMP-3) in the pathology of early and late OA.
  
  
  METHODS
  The role of synovial macrophages in MMP-mediated damage in OA was studied by depleting synovial macrophages prior to elicitation of a collagenase-induced instability model of OA. The expression of MMP in synovium and cartilage was monitored using TaqMan analysis. In spontaneous and induced OA, cartilage pathology was scored in MMP-3-knockout mice and control mice, by histologic assessment and VDIPEN staining.
  
  
  RESULTS
  On day 14 following induction of OA, MMP-mediated neoepitopes were detected in cartilage from mice with mild experimental OA (mean +/- SD positively stained surface area 20 +/- 3.2%). Remarkably, by depleting synovial macrophages prior to induction of OA, the generation of MMP-induced neoepitopes was largely prevented (mean +/- SD positively stained surface area 5 +/- 1%; P< 0.001), indicating an important role for synovial macrophages in the occurrence of MMP-mediated cartilage damage. We observed a strong decrease in MMP-3 and MMP-9 expression in synovial but not cartilage tissue in macrophage-depleted joints. Among 2-year-old mice, spontaneous OA-like changes in the lining layer were significantly decreased in MMP-3-knockout mice compared with control mice. Even more striking was the 67% reduction in the occurrence of severe cartilage damage in MMP-3-knockout mice. In addition, MMP-mediated VDIPEN expression was significantly decreased, indicating reduced MMP-mediated cartilage breakdown.
  
  
  CONCLUSIONS
  The results of this study prove that MMP-3 is involved in the generation of severe cartilage damage in murine OA. Synovial macrophages are crucial in early MMP activity and appear to mediate MMP production in synovium rather than cartilage.
authors.affiliation: Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands. a.blom@reuma.umcn.nl
authors.forename: Arjen B
authors.initials: AB
authors.lastname: Blom
authors.forename: Peter L
authors.initials: PL
authors.lastname: van Lent
authors.forename: Sten
authors.initials: S
authors.lastname: Libregts
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Holthuysen
authors.forename: Peter M
authors.initials: PM
authors.lastname: van der Kraan
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000201:enzymology* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology
chemical_list: D050071:Bone Density Conservation Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C093378:peptide VDIPEN; D004002:Clodronic Acid; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9