Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase

Eun Hee Hong, Su Jae Lee, Jae Sung Kim, Kee Ho Lee, Hong Duck Um, Jae-Hong Kim, Song Ja Kim, Jong Il Kim, Sang Gu Hwang

Research output: Contribution to journalArticle

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Abstract

Radiotherapy is increasingly used in the treatment of joint diseases, but limited information is available on the effects of radiation on cartilage. Here, we characterize the molecular mechanisms leading to cellular senescence in irradiated primary cultured articular chondrocytes. Ionizing radiation (IR) causes activation of ERK, in turn generating intracellular reactive oxygen species (ROS) with induction of senescence-associated β-galactosidase (SA-β-gal) activity. ROS activate p38 kinase, which further promotes ROS generation, forming a positive feedback loop to sustain ROS-p38 kinase signaling. The ROS inhibitors, nordihydroguaiaretic acid and GSH, suppress phosphorylation of p38 and cell numbers positive for SA-β-gal following irradiation. Moreover, inhibition of the ERK and p38 kinase pathways leads to blockage of IR-induced SA-β-gal activity via reduction of ROS generation. Although JNK is activated by ROS, this pathway is not associated with cellular senescence of chondrocytes. Interestingly, IR triggers down-regulation of SIRT1 protein expression but not the transcript level, indicative of post-transcriptional cleavage of the protein. SIRT1 degradation is markedly blocked by SB203589 or MG132 after IR treatment, suggesting that cleavage occurs as a result of binding with p38 kinase, followed by processing via the 26 S proteasomal degradation pathway. Overexpression or activation of SIRT1 significantly reduces the IR-induced senescence phenotype, whereas inhibition of SIRT1 activity induces senescence. Based on these findings, we propose that IR induces cellular senescence of articular chondrocytes by negative post-translational regulation of SIRT1 via ROS-dependent p38 kinase activation.

Original languageEnglish
Pages (from-to)1283-1295
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
Publication statusPublished - 2010 Jan 19

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Cell Aging
Ionizing radiation
Chondrocytes
Ionizing Radiation
Reactive Oxygen Species
Phosphotransferases
Joints
Galactosidases
Chemical activation
Masoprocol
Degradation
Phosphorylation
MAP Kinase Signaling System
Joint Diseases
Radiation Effects
Radiotherapy
Cartilage
Proteins
Down-Regulation
Cell Count

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase. / Hong, Eun Hee; Lee, Su Jae; Kim, Jae Sung; Lee, Kee Ho; Um, Hong Duck; Kim, Jae-Hong; Kim, Song Ja; Kim, Jong Il; Hwang, Sang Gu.

In: Journal of Biological Chemistry, Vol. 285, No. 2, 19.01.2010, p. 1283-1295.

Research output: Contribution to journalArticle

Hong, Eun Hee ; Lee, Su Jae ; Kim, Jae Sung ; Lee, Kee Ho ; Um, Hong Duck ; Kim, Jae-Hong ; Kim, Song Ja ; Kim, Jong Il ; Hwang, Sang Gu. / Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 2. pp. 1283-1295.
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