The inhibition of subchondral bone resorption in the early phase of experimental dog osteoarthritis by licofelone is associated with a reduction in the synthesis of MMP-13 and cathepsin K.
OBJECTIVE
To evaluate the morphological changes that take place in the subchondral bone and calcified cartilage zone in the experimental anterior cruciate ligament (ACL) dog model of osteoarthritis (OA) and analyze concomitant changes in the level of MMP-13 and cathepsin K, as well as examine the therapeutic effects of licofelone, a lipoxygenase (LO)/cyclooxygenase (COX) inhibitor, on these morphological and biochemical changes.


METHODS
Experimental group 1 underwent sectioning of the ACL of the right knee with no active treatment (placebo group). Experimental groups 2 and 3 underwent sectioning of the ACL of the right knee and were administered therapeutic concentrations of licofelone (2.5 or 5.0 mg/kg/day p.o., respectively) for 8 weeks, beginning the day following surgery. Group 4 consisted of untreated dogs used as normal control. Specimens of subchondral bone including the calcified cartilage were selected from lesional and non-lesional areas of OA tibial plateaus. Specimens were processed for static morphometric analysis and immunohistochemical analysis for MMP-13 and cathepsin K.


RESULTS
As indicated by a reduction in bone surface and trabecular thickness, a significant loss of subchondral bone occurred in OA dogs. These changes were associated with an increased level of MMP-13 synthesis by bone cells and an increase in the osteoclast population that stained strongly positive for cathepsin K and MMP-13. Changes were much more pronounced in the specimens taken from the lesional areas. Treatment with licofelone decreased, in a dose-dependent manner, the OA bone morphological changes at the same time it reduced the level of MMP-13 in bone cells and the number of cathepsin K and MMP-13 positive osteoclasts.


CONCLUSIONS
Increased bone loss and bone resorption is associated with the development of OA cartilage lesions. Licofelone treatment was found to prevent the morphological and biochemical changes seen in early experimental OA effectively. These findings may help explain the mechanisms by which this drug could exert its possible effect on the development of OA.
Pelletier
Jean-Pierre
JP
Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montreal, Hôpital Notre-Dame, Montreal, Quebec, Canada H2L 4M1. dr@jppelletier.ca
Boileau
Christelle
C
Brunet
Julie
J
Boily
Martin
M
Lajeunesse
Daniel
D
Reboul
Pascal
P
Laufer
Stefan
S
Martel-Pelletier
Johanne
J
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017364:Collagenases / Q000096:biosynthesis; D004285:Dogs; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*
D000085:Acetates; D061965:Matrix Metalloproteinase Inhibitors; D011758:Pyrroles; D002403:Cathepsins; D056657:Cathepsin K; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C088092:licofelone