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.

Objective Protein kinase Cd (PKCd) 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 PKCd, in intervertebral disc tissue homeostasis. Methods Using in vitro, ex vivo, and in vivo techniques, we evaluated the pathophysiologic role of the PKCd pathway by examining 1) proteoglycan deposition, 2) matrix-degrading enzyme production and activity, 3) downstream signaling pathways regulated by PKCd, and 4) the effect on in vivo models of disc degeneration in genetically engineered PKCd-knockout mice. Results Studies of pathway-specific inhibitors revealed a vital role of the PKCd/MAPK (ERK, p38, JNK) axis and NF-?B in disc homeostasis. Accordingly, in an in vivo model of disc injury, PKCd-knockout mice were markedly resistant to disc degeneration. Conclusion Suppression of the PKCd 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 PKCd cascade in the future.