Oral treatment with PD-0200347, an alpha2delta ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible nitric oxide synthase gene expression and synthesis in cartilage chondrocytes.
OBJECTIVE
To examine the in vivo effects of PD-0200347, an alpha(2)delta ligand of voltage-activated Ca(2+) channels and a compound chemically related to pregabalin and gabapentin, on the development of cartilage structural changes in an experimental dog model of osteoarthritis (OA). The effects of PD-0200347 on the major pathways involved in OA cartilage degradation, including matrix metalloproteinases (MMPs) and the inducible form of nitric oxide synthase (iNOS), were also studied.


METHODS
OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were randomly distributed into 3 groups and treated orally with either 1) placebo, 2) 15 mg/kg/day of PD-0200347, or 3) 90 mg/kg/day of PD-0200347. Dogs were killed 12 weeks after surgery. The severity of the lesions was scored macroscopically and histologically. Cartilage specimens from the femoral condyles and tibial plateaus were processed for RNA extraction and quantitative reverse transcription-polymerase chain reaction (RT-PCR) or immunohistochemistry. Specific probes and antibodies were used to study the messenger RNA and protein levels of iNOS, MMP-1, MMP-3, and MMP-13.


RESULTS
No clinical signs of drug toxicity were noted in the treated animals. Treatment with PD-0200347 at both dosages tested (15 and 90 mg/kg/day) reduced the development of cartilage lesions. There was a reduction in the score of lesions, with a statistically significant (P = 0.01) difference when the highest dosage of the drug was administered. The reduction in the score was mainly related to a decrease in the surface size of the lesions. Quantitative RT-PCR showed that PD-0200347 significantly reduced the expression of MMP-13, a key mediator in OA. Immunohistochemical analyses showed that treatment with PD-0200347 significantly reduced the synthesis of all key OA mediators studied.


CONCLUSIONS
This study demonstrated the efficacy of PD-0200347 in reducing the progression of cartilage structural changes in a dog model of OA. It also showed that this effect is linked to the inhibition of the major pathophysiologic mediators responsible for cartilage degradation.
Boileau
Christelle
C
Notre-Dame Hospital, University of Montreal Hospital Centre, Montreal, Quebec, Canada.
Martel-Pelletier
Johanne
J
Brunet
Julie
J
Tardif
Ginette
G
Schrier
Denis
D
Flory
Craig
C
El-Kattan
Ayman
A
Boily
Martin
M
Pelletier
Jean-Pierre
JP
D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage*; D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D019902:Chondrocytes / Q000201:enzymology*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D000077206:Gabapentin; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D010003:Osteoarthritis / Q000473:pathology / Q000517:prevention & control*; D000069583:Pregabalin; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; C497431:PD-0200347; D012333:RNA, Messenger; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D045726:Metalloproteases