p38 Kinase-dependent and -independent Inhibition of Protein Kinase C ζ and -α Regulates Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes

• Published in: The Journal of biological chemistry 2002-08, Vol.277 (33), p.30375-30381
• Main Authors: Kim, Song-Ja, Kim, Han-Gyul, Oh, Chun-Do, Hwang, Sang-Gu, Song, Woo-Keun, Yoo, Yung-Joon, Kang, Shin-Sung, Chun, Jang-Soo
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis - physiology; Base Sequence; Cartilage, Articular - cytology; Cartilage, Articular - drug effects; Caspase 3; Caspases - metabolism; Cell Differentiation - physiology; Chondrocytes - cytology; Chondrocytes - drug effects; DNA Primers; Enzyme Activation; Hydrolysis; Isoenzymes - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Nitroprusside - pharmacology; p38 Mitogen-Activated Protein Kinases; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - chemistry; Protein Kinase C-alpha; Rabbits
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M205193200

In articular chondrocytes, nitric oxide (NO) production triggers dedifferentiation and apoptotic cell death that is regulated by the converse functions of two mitogen-activated protein kinase subtypes, extracellular signal-regulated kinase (ERK) and p38 kinase. Since protein kinase C (PKC) transduces signals that influence differentiation, survival, and apoptosis of various cell types, we investigated the roles and underlying molecular mechanisms of action of PKC isoforms in NO-induced dedifferentiation and apoptosis of articular chondrocytes. We report here that among the expressed isoforms, activities of PKCα and -ζ were reduced during NO-induced dedifferentiation and apoptosis. Inhibition of PKCα activity was independent of NO-induced activation of ERK or p38 kinase and occurred due to blockage of expression. On the other hand, PKCζ activity was inhibited as a result of NO-induced p38 kinase activation and was observed prior to proteolytic cleavage by a caspase-mediated process to generate enzymatically inactive fragments. Inhibition of PKCα or -ζ activities potentiated NO-induced apoptosis, whereas ectopic expression of these isoforms significantly reduced the number of apoptotic cells and blocked dedifferentiation. Ectopic expression of PKCα or -ζ did not affect p38 kinase or ERK but inhibited the p53 accumulation and caspase-3 activation that are required for NO-induced apoptosis of chondrocytes. Therefore, our results collectively indicate that p38 kinase-independent and -dependent inhibition of PKCα and -ζ, respectively, regulates NO-induced apoptosis and dedifferentiation of articular chondrocytes.