Open AccessThe pathophysiologic role of the protein kinase Cδ pathway in the intervertebral discs of rabbits and mice: In vitro, ex vivo, and in vivo studies
Author(s) -
Ellman Michael B.,
Kim JaeSung,
An Howard S.,
Kroin Jeffrey S.,
Li Xin,
Chen Di,
Yan Dongyao,
Buechter Doug D.,
Nakayama Keiichi,
Liu Bo,
Morgan Stephanie,
Im HeeJeong
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34337
Subject(s) - protein kinase c , in vivo , ex vivo , microbiology and biotechnology , knockout mouse , intervertebral disc , mapk/erk pathway , p38 mitogen activated protein kinases , signal transduction , kinase , chemistry , biology , biochemistry , anatomy , receptor
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.