title: Licofelone reduces progression of structural changes in a canine model of osteoarthritis under curative conditions: effect on protease expression and activity.
abstract: OBJECTIVE
  We investigated the effectiveness of licofelone, a combined 5-lipoxygenase and cyclooxygenase inhibitor, on structural changes in the anterior cruciate ligament (ACL) experimental dog model of osteoarthritis (OA) under therapeutic conditions. The effect of drug treatment on the expression and activity of metalloproteases in the OA cartilage was also studied.
  
  
  METHODS
  The cranial cruciate ligament of the right stifle joint was surgically sectioned in 14 dogs to create OA lesions. Of these dogs, 7 received placebo treatment and served as OA controls, while 7 were treated with licofelone 2.5 mg/kg twice daily for an 8-week period, starting 4 weeks after surgery. At necropsy, macroscopic evaluations were made of the size of osteophytes and the severity of cartilage lesions on femoral condyles and tibial plateaus. Collagenase and other metalloprotease activity levels in cartilage were measured. Levels of gene expression of matrix metalloprotease (MMP-1), MMP-13, cathepsin K, and ADAMTS-5 were quantified by RT-PCR.
  
  
  RESULTS
  Licofelone treatment reduced the development of osteophytes and size of cartilage lesions on the femoral condyles and on the tibial plateaus (p < 0.04). Drug treatment also significantly decreased collagenase (p < 0.02) and metalloprotease (p < 0.04) activities, as well as the levels of gene expression of MMP-1 (p < 0.01), MMP-13 (p < 0.05), cathepsin K, and ADAMTS-5 (p = 0.01).
  
  
  CONCLUSIONS
  Under therapeutic conditions licofelone showed the ability to reduce the progression of structural changes in experimental dog OA. This beneficial effect is likely mediated through decrease in the synthesis of a number of catabolic factors, including proteolytic enzymes, involved in cartilage breakdown.
authors.affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, Quebec, Canada.
authors.forename: Maxim
authors.initials: M
authors.lastname: Moreau
authors.forename: Christelle
authors.initials: C
authors.lastname: Boileau
authors.forename: Johanne
authors.initials: J
authors.lastname: Martel-Pelletier
authors.forename: Julie
authors.initials: J
authors.lastname: Brunet
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelletier
mesh_terms: D000085:Acetates / Q000627:therapeutic use*; D000818:Animals; D016118:Anterior Cruciate Ligament / Q000601:surgery; D002358:Cartilage, Articular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000627:therapeutic use*; D013264:Stifle / Q000601:surgery
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D011758:Pyrroles; D045726:Metalloproteases; D017364:Collagenases; C088092:licofelone