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PD-0200347, an α2δ ligand of the voltage gated calcium channel, inhibits in vivo activation of the Erk1/2 pathway in osteoarthritic chondrocytes: a PKCα dependent effect
  1. C Boileau1,
  2. J Martel-Pelletier1,
  3. J Brunet1,
  4. D Schrier2,
  5. C Flory2,
  6. M Boily1,
  7. J-P Pelletier1
  1. 1Osteoarthritis Research Unit, Notre-Dame Hospital, University of Montreal Hospital Centre, Montreal, Quebec, Canada, H2L 4M1
  2. 2Pfizer Global Research and Development, Ann Arbor, MI 48105, USA
  1. 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

Abstract

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
  • chondrocytes
  • osteoarthritis
  • calcium channels
  • PD-0200347
  • PKC

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Footnotes

  • 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.

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