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.
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.
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DOI：
10.1002/art.34337
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发表时间：
2012-06
影响因子：
--
通讯作者：
Im, Hee-Jeong
中科院分区：
文献类型：
--
作者：
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
PKCδ活化被认为是人关节软骨细胞中基质降解酶产生的主要限速步骤。然而，PKC途径，特别是PKCδ，在椎间盘组织稳态中的作用尚未得到评估。使用体外、离体和体内技术，我们通过检查（i）蛋白多糖沉积;（ii）基质降解酶的产生和活性;（iii）PKCδ调节的下游信号传导通路;以及（iv）对基因工程PKCδ敲除小鼠体内椎间盘退变模型的影响，评估了PKCδ通路的病理生理学作用。通路特异性抑制剂研究揭示了PKCδ-MAPK（ERK，p38，JNK）轴和NFκB B在椎间盘稳态中的重要作用。因此，在体内椎间盘损伤模型中，PKCδ敲除小鼠对椎间盘退变具有显著抗性。抑制PKCδ通路可能有利于预防和/或治疗椎间盘退变，这些发现为将来PKCδ级联通路特异性抑制剂的潜在治疗作用提供了证据。
PKCδ activation was found to be a principal rate-limiting step in matrix-degrading enzyme production in human articular chondrocytes. However, the role of the PKC pathways, specifically PKCδ, has not yet been assessed in intervertebral disc tissue homeostasis. Using in vitro, ex vivo, and in vivo techniques, we evaluated the pathophysiological role of the PKCδ pathway by examining (i) proteoglycan deposition; (ii) matrix-degrading enzyme production and activity; (iii) downstream signaling pathways regulated by PKCδ; and (iv) the effect on in vivo models of disc degeneration in genetically-engineered PKCδ knockout mice. Pathway-specific inhibitor studies reveal a vital role of PKCδ-MAPK (ERK, p38, JNK) axis and NFκB in disc homeostasis. Accordingly, PKCδ knockout mice are markedly resistant to disc degeneration in a disc injury model in vivo. Suppression of the PKCδ pathway may be beneficial in the prevention and/or treatment of disc degeneration, and these findings provide evidence for the potential therapeutic role of pathway-specific inhibitors of the PKCδ cascade in the future.
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影响因子：
3.3
作者：
Klinger, James R.;Murray, Josh D.;Harrington, Elizabeth O.
通讯作者：
Harrington, Elizabeth O.
影响因子：
3
作者：
An, HS;Thonar, EJMA;Masuda, K
通讯作者：
Masuda, K
DOI：
10.1073/pnas.191369098
发表时间：
2001-09-25
影响因子：
11.1
作者：
Chen, L;Hahn, H;Mochly-Rosen, D
通讯作者：
Mochly-Rosen, D
影响因子：
7.3
作者：
Le Maitre, CL;Freemont, AJ;Hoyland, JA
通讯作者：
Hoyland, JA
影响因子：
4.8
作者：
Muddasani, Prasuna;Norman, Jim C.;Im, Hee-Jeong
通讯作者：
Im, Hee-Jeong