title: ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status.
abstract: Nitric oxide regulates cartilage destruction by causing dedifferentiation and apoptosis of chondrocytes. We investigated the role of the mitogen-activated protein kinase subtypes, extracellular signal-regulated protein kinase (ERK)-1/2, and p38 kinase in NO-induced apoptosis of rabbit articular chondrocytes and their involvement in dedifferentiation. Generation of NO with sodium nitroprusside (SNP) caused dedifferentiation, as indicated by the inhibition of type II collagen expression and proteoglycan synthesis. NO additionally caused apoptosis, accompanied by p53 accumulation and caspase-3 activation. SNP treatment stimulated activation of ERK-1/2 and p38 kinase. Inhibition of ERK-1/2 with PD98059 rescued SNP-induced dedifferentiation but enhanced apoptosis up to 2-fold, whereas inhibition of p38 kinase with SB203580 enhanced dedifferentiation, with significant blockage of apoptosis. The stimulation of apoptosis by ERK inhibition was accompanied by increased p53 accumulation and caspase-3 activity, whereas the inhibitory effect of p38 kinase blockade was associated with reduced p53 accumulation and caspase-3 activity. Our results indicate that NO-induced p38 kinase functions as an induction signal for apoptosis and in the maintenance of chondrocyte phenotype, whereas ERK activity causes dedifferentiation and operates as an anti-apoptotic signal. NO generation is less proapoptotic in chondrocytes that are dedifferentiated by serial monolayer culture or phorbol ester treatment. NO-induced p38 kinase activity is low in dedifferentiated cells compared with that in differentiated chondrocytes, with lower levels of p53 accumulation and caspase-3 activity. Our findings collectively suggest that ERK-1/2 and p38 kinase oppositely regulate NO-induced apoptosis of chondrocytes, in association with p53 accumulation, caspase-3 activation, and differentiation status.
authors.affiliation: National Research Laboratory, Department of Life Science, Kwangju Institute of Science and Technology, Kwangju 500-712, Korea.
authors.forename: Song-Ja
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Ju
authors.forename: Chun-Do
authors.initials: CD
authors.lastname: Oh
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Yoon
authors.forename: Woo Keun
authors.initials: WK
authors.lastname: Song
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Yung Joon
authors.initials: YJ
authors.lastname: Yoo
authors.forename: Ok-Sun
authors.initials: OS
authors.lastname: Bang
authors.forename: Shin-Sung
authors.initials: SS
authors.lastname: Kang
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D007093:Imidazoles / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D020030:Nitric Oxide Donors; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D009599:Nitroprusside; D009569:Nitric Oxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020169:Caspases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one