The pathophysiologic role of the protein kinase Cδ pathway in the intervertebral discs of rabbits and mice: in vitro, ex vivo, and in vivo studies

Arthritis Rheum. 2012 Jun;64(6):1950-9. doi: 10.1002/art.34337. Epub 2011 Dec 12.

Abstract

Objective: Protein kinase Cδ (PKCδ) activation has been shown to be a principal rate-limiting step in matrix-degrading enzyme production in human articular chondrocytes. The aim of this study was to assess the role of the PKC pathways, specifically PKCδ, in intervertebral disc tissue homeostasis.

Methods: Using in vitro, ex vivo, and in vivo techniques, we evaluated the pathophysiologic role of the PKCδ pathway by examining 1) proteoglycan deposition, 2) matrix-degrading enzyme production and activity, 3) downstream signaling pathways regulated by PKCδ, and 4) the effect on in vivo models of disc degeneration in genetically engineered PKCδ-knockout mice.

Results: Studies of pathway-specific inhibitors revealed a vital role of the PKCδ/MAPK (ERK, p38, JNK) axis and NF-κB in disc homeostasis. Accordingly, in an in vivo model of disc injury, PKCδ-knockout mice were markedly resistant to disc degeneration.

Conclusion: Suppression of the PKCδ pathway may be beneficial in the prevention and/or treatment of disc degeneration. The results of this study provide evidence for a potential therapeutic role of pathway-specific inhibitors of the PKCδ cascade in the future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cells, Cultured
  • Chondrocytes / drug effects
  • Chondrocytes / enzymology*
  • Intervertebral Disc / drug effects
  • Intervertebral Disc / enzymology*
  • Intervertebral Disc Degeneration / enzymology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism*
  • Proteoglycans / metabolism
  • Rabbits
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

  • NF-kappa B
  • Proteoglycans
  • Protein Kinase C-delta