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PD-0200347, an ₂ ligand of the voltage gated calcium channel, inhibits in vivo activation of the Erk1/2 pathway in osteoarthritic chondrocytes: a PKC dependent effect

C Boileau¹, J Martel-Pelletier¹, J Brunet¹, D Schrier², C Flory², M Boily¹, J-P Pelletier¹

¹ Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal Hospital Centre, Montreal, Quebec, Canada, H2L 4M1
² Pfizer Global Research and Development, Ann Arbor, MI 48105, USA

Correspondence to:
Dr J-P Pelletier
Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal Hospital Centre, 1560 Sherbrooke Street East, Montreal, Quebec, Canada, H2L 4M1; dr{at}jppelletier.ca

Objective: To explore the in vivo effects of PD-0200347, an ₂ 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 PKC, 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 PKC, 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.

Abbreviations: GABA, -aminobutyric acid; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; OA, osteoarthritis; PBS, phosphate buffered saline; PKC, protein kinase C; ROS, reactive oxygen species

Keywords: chondrocytes; osteoarthritis; calcium channels; PD-0200347; PKC

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