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

Michael B. Ellman, Jae Sung Kim, Howard S. An, Jeffrey S. Kroin, Xin Li, Di Chen, Dongyao Yan, Doug D. Buechter, Keiichi Nakayama, Bo Liu, Stephanie Morgan, Hee Jeong Im

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1950-1959
Number of pages10
JournalArthritis and rheumatism
Volume64
Issue number6
DOIs
Publication statusPublished - Jun 1 2012

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Intervertebral Disc
Protein Kinase C
Rabbits
Intervertebral Disc Degeneration
Knockout Mice
Homeostasis
In Vitro Techniques
p38 Mitogen-Activated Protein Kinases
Proteoglycans
Enzymes
Chondrocytes
Joints

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

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. / Ellman, Michael B.; Kim, Jae Sung; An, Howard S.; Kroin, Jeffrey S.; Li, Xin; Chen, Di; Yan, Dongyao; Buechter, Doug D.; Nakayama, Keiichi; Liu, Bo; Morgan, Stephanie; Im, Hee Jeong.

In: Arthritis and rheumatism, Vol. 64, No. 6, 01.06.2012, p. 1950-1959.

Research output: Contribution to journalArticle

Ellman, MB, Kim, JS, An, HS, Kroin, JS, Li, X, Chen, D, Yan, D, Buechter, DD, Nakayama, K, Liu, B, Morgan, S & Im, HJ 2012, '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 and rheumatism, vol. 64, no. 6, pp. 1950-1959. https://doi.org/10.1002/art.34337
Ellman, Michael B. ; Kim, Jae Sung ; An, Howard S. ; Kroin, Jeffrey S. ; Li, Xin ; Chen, Di ; Yan, Dongyao ; Buechter, Doug D. ; Nakayama, Keiichi ; Liu, Bo ; Morgan, Stephanie ; Im, Hee Jeong. / 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. In: Arthritis and rheumatism. 2012 ; Vol. 64, No. 6. pp. 1950-1959.
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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.",
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