New strategies for the in vivo regulation of metalloprotease gene expression in osteoarthritis chondrocytes by inflammatory mediators

Objective

To study the effect of oral treatment with PD200347, a gabapentinoid (GBP), on osteoarthritis (OA) progression and OA mediators, matrix metalloproteases (MMPs) and the inducible form of nitric oxide synthase (iNOS) expression in a dog experimental model of OA.

Methods

OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were divided into three groups after surgery: group 1, placebo-treated (OA); group 2, oral treatment with 15 mg/kg/day GBP; and group 3, oral treatment with 90 mg/kg/day GBP. Dogs were killed 8 weeks after surgery. The severity of lesions was scored macroscopically and histologically. Cartilage specimens from femoral condyles and tibial plateaus were processed for RNA extraction and quantitative RT-PCR or immunohistochemistry. Specific probes and specific antibodies were used to study IL-1β, iNOS, MMP-1, MMP-3 and MMP-13 mRNA and protein levels, respectively.

Results

GBP treatment at both dosages tested (15 or 90 mg/kg/day) dose-dependently reduced the development of cartilage lesions. Quantitative RT-PCR and immunohistochemical analysis showed that GBP treatment also significantly reduced key OA mediator (IL-1β, iNOS, MMP-1, MMP-3 and MMP-13) gene expression and synthesis.

Conclusion

This study demonstrated for the first time the effectiveness of a GBP on the reduction of the development of structural changes in the dog OA model. The effect of GBP is mediated through the inhibition, at the transcriptional level, of major mediators of pathophysiological pathways.