title: Osteochondral angiogenesis and increased protease inhibitor expression in OA.
abstract: OBJECTIVE
  Normal cartilage is resistant to vascular invasion and anti-angiogenic protease inhibitors may contribute to its avascular status. We hypothesized that dysregulated expression of four key anti-angiogenic protease inhibitors may contribute to increased osteochondral vascularity in osteoarthritis (OA).
  
  
  METHODS
  Medial tibial plateaux from OA patients (n=40) were compared with those from non-arthritic controls collected post-mortem (PM, n=10). Immunohistochemistry was performed for protease inhibitors TIMP-1, TIMP-3, PAI-1 and SLPI and the pro-angiogenic factor vascular endothelial growth factor (VEGF). Immunoreactivity in articular chondrocytes was scored. Chondropathy was measured as a modified Mankin score, and osteochondral vascular density as number of channels crossing each mm of tidemark. Non-parametric analyses were used for all data.
  
  
  RESULTS
  All protease inhibitors and VEGF were localised to chondrocytes near the articular surface, less often in the middle zone, and rarely to deep chondrocytes. Scores for VEGF, TIMP-1, TIMP-3, SLPI and PAI-1 were all increased in OA compared with PM, and higher scores were associated with greater chondropathy. Chondrocyte expression of VEGF was associated with higher osteochondral vascular density (r=0.32, P<0.05), whereas protease inhibitors were not.
  
  
  CONCLUSIONS
  The resistance of normal articular cartilage to vascular invasion may be more due to its matrix environment than ongoing protease inhibitor expression. Upregulation of protease inhibitors by superficial chondrocytes in OA may moderate the angiogenic effects of growth factors such as VEGF. However, failure of deep chondrocytes to express anti-angiogenic protease inhibitors may permit vascular invasion into the articular cartilage.
authors.affiliation: Academic Rheumatology, University of Nottingham, Clinical Sciences Building, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Fransès
authors.forename: D F
authors.initials: DF
authors.lastname: McWilliams
authors.forename: P I
authors.initials: PI
authors.lastname: Mapp
authors.forename: D A
authors.initials: DA
authors.lastname: Walsh
mesh_terms: D019902:Chondrocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism*; D013977:Tibia / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; C117201:STOML1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A