ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status

Song Ja Kim, Ng Won Ju, Chun Do Oh, Young Mee Yoon, Woo Keun Song, Jae Hong Kim, Yung Joon Yoo, Ok Sun Bang, Shin Sung Kang, Jang Soo Chun

Research output: Contribution to journalArticle

206 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1332-1339
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number2
DOIs
Publication statusPublished - 2002 Jan 11

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status'. Together they form a unique fingerprint.

  • Cite this