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Oral treatment with PD-0200347, an α2δ ligand, reduces the development of experimental osteoarthritis by inhibiting the chondrocytes metalloproteases and inducible nitric oxide synthase gene expression and synthesis
Arthritis Res Ther volume 6, Article number: 52 (2004)
The aim of this study was to examine the in vivo effects of PD-0200347, an α2δ ligand of voltage-activated Ca2+ channels and a member of the gabapentin family, on the development of cartilage structural changes in an experimental osteoarthritis (OA) dog model. We examined its effects on the major pathways involved in OA cartilage degradation including metalloproteases (MMPs), the inducible form of nitric oxide synthase (iNOS) and IL-1β.
OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were divided into three groups and treated orally with placebo, with 15 mg/kg/day PD-0200347, or with 90 mg/kg/day PD-0200347. Dogs were sacrificed 12 weeks after surgery. The severity of lesions was scored macroscopically and histologically. Cartilage specimens from femoral condyles and tibial plateaus were processed for quantitative PCR and immunohistochemistry. Specific probes and antibodies were used to study IL-1β, iNOS, MMP-1, MMP-3 and MMP-13 mRNA and protein levels, respectively.
No clinical signs of drug toxicity were noted in the treated animals. PD-0200347 treatment at both dosages tested (15 or 90 mg/kg/day) reduced the development of cartilage lesions. There was a reduction in the score of lesions, and statistical significance (P < 0.01) was reached at the highest dosage of the drug. This score reduction was mainly related to the decrease in the lesion surface size. Quantitative PCR and immunohistochemical analyses showed that PD-0200347 treatment also significantly reduced key OA mediators, IL-1β, iNOS, MMP-1, MMP-3 and MMP-13 gene expression and synthesis.
This study demonstrated the efficacy of PD-0200347 at reducing the progression of cartilage structural changes in an OA dog model. It also showed that this effect is linked to the inhibition, at the transcriptional level, of the major pathophysiological mediators. The mechanism of action could be related to a significant reduction of Ca2+ current amplitude via voltage-gated calcium channels, which in turn downregulates the downstream signaling pathways.