Objective: To explore the in vivo effects of PD-0200347, an α2δ ligand of voltage gated Ca2+ channels, on cell signalling in osteoarthritic (OA) chondrocytes from an experimental dog model, and examine the effect of PD-0200347 on the major signalling pathways involved in OA cartilage degradation.
Methods: OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were divided into three groups and treated orally with (a) placebo; (b) 15 mg/kg/day PD-0200347, or (c) 90 mg/kg/day PD-0200347. The animals were killed 12 weeks after surgery. Cartilage specimens from femoral condyles and tibial plateaus were processed for immunohistochemistry. Specific antibodies against the phosphorylated form of PKCα, Ras, c-Raf, the MAP kinases Erk1/2, p38, JNK, and the transcription factors, CREB and Elk-1, were used.
Results: Levels of all the tested signalling mediators were increased in the placebo treated (OA) group compared with the normal group. PD-0200347 treatment significantly reduced the levels of the active forms of PKCα, c-Raf, Erk1/2, and Elk-1; however, the levels of the active forms of Ras, p38, JNK, and CREB were not affected by the PD-0200347 treatment.
Conclusion: The action of PD-0200347 on OA chondrocytes is probably mediated through the inhibition of Erk1/2 activation via a Ras independent mechanism. This effect is associated with reduction of the activation of transcription factors such as Elk-1, which leads to the inhibition of the induction of the major catabolic factors involved in the degradation process of OA cartilage.
- GABA, γ-aminobutyric acid
- iNOS, inducible nitric oxide synthase
- MMP, matrix metalloproteinase
- OA, osteoarthritis
- PBS, phosphate buffered saline
- PKC, protein kinase C
- ROS, reactive oxygen species
- calcium channels
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Published Online First 25 October 2005
Competing interests: Denis Schrier and Craig Flory are employees of Pfizer Global Research and Development.
Jean-Pierre Pelletier and Johanne Martel-Pelletier are consultants for Pfizer Global Research and Development.