PKR promotes oxidative stress and apoptosis of human articular chondrocytes by causing mitochondrial dysfunction through p38 MAPK activation—PKR activation causes apoptosis in human chondrocytes

Ching Hou Ma, Chin Hsien Wu, I. Ming Jou, Yuan Kun Tu, Ching Hsia Hung, Wan Ching Chou, Yun Ching Chang, Pei Ling Hsieh, Kun Ling Tsai

Research output: Contribution to journalArticle

Abstract

Osteoarthritis (OA) is one of the most common types of arthritis in the elderly people. It has been known that chondrocyte apoptosis occurs in OA cartilage; however, the detailed molecular mechanism remains unclear. In the current study, we aimed to elucidate the role of double-stranded RNA-dependent protein kinase R (PKR) in the TNF-α-caused apoptosis in chondrocytes. Human articular chondrocytes were digested from cartilages of OA subjects who accepted arthroplastic knee surgery. Our results showed that phosphorylation of p38 MAPK was increased after TNF-α stimulation or PKR activation using poly (I:C), and TNF-α-induced p38 MAPK upregulation was inhibited by PKR inhibition, suggesting phosphor-p38 MAPK was regulated by PKR. Moreover, we found that PKR participated in the p53-dependent destruction of AKT following activation of p38 MAPK. The inhibition of AKT led to the reduced expression of PGC-1α, which resulted in mitochondrial dysfunction and increased oxidative stress. We showed that the reduction of oxidative stress using antioxidant Mito TEMPO lowered the TNF-α-induced caspase-3 activation and TUNEL-positive apoptotic cells. The diminished apoptotic response was also observed after repression of PKR/p38 MAPK/p53/AKT/PGC-1α signaling. Taken together, we demonstrated that the aberrant mitochondrial biogenesis and increased oxidative stress in chondrocytes after TNF-α stimulation were mediated by PKR, which may contribute to the chondrocyte apoptosis and cartilage degeneration in OA.

Original languageEnglish
Article number370
JournalAntioxidants
Volume8
Issue number9
DOIs
Publication statusPublished - 2019 Sep

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Oxidative stress
p38 Mitogen-Activated Protein Kinases
Chondrocytes
Protein Kinases
Oxidative Stress
Joints
Chemical activation
Apoptosis
Osteoarthritis
Cartilage
eIF-2 Kinase
Poly I-C
Phosphorylation
Double-Stranded RNA
In Situ Nick-End Labeling
Organelle Biogenesis
Caspase 3
Phosphors
Surgery
Arthritis

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

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title = "PKR promotes oxidative stress and apoptosis of human articular chondrocytes by causing mitochondrial dysfunction through p38 MAPK activation—PKR activation causes apoptosis in human chondrocytes",
abstract = "Osteoarthritis (OA) is one of the most common types of arthritis in the elderly people. It has been known that chondrocyte apoptosis occurs in OA cartilage; however, the detailed molecular mechanism remains unclear. In the current study, we aimed to elucidate the role of double-stranded RNA-dependent protein kinase R (PKR) in the TNF-α-caused apoptosis in chondrocytes. Human articular chondrocytes were digested from cartilages of OA subjects who accepted arthroplastic knee surgery. Our results showed that phosphorylation of p38 MAPK was increased after TNF-α stimulation or PKR activation using poly (I:C), and TNF-α-induced p38 MAPK upregulation was inhibited by PKR inhibition, suggesting phosphor-p38 MAPK was regulated by PKR. Moreover, we found that PKR participated in the p53-dependent destruction of AKT following activation of p38 MAPK. The inhibition of AKT led to the reduced expression of PGC-1α, which resulted in mitochondrial dysfunction and increased oxidative stress. We showed that the reduction of oxidative stress using antioxidant Mito TEMPO lowered the TNF-α-induced caspase-3 activation and TUNEL-positive apoptotic cells. The diminished apoptotic response was also observed after repression of PKR/p38 MAPK/p53/AKT/PGC-1α signaling. Taken together, we demonstrated that the aberrant mitochondrial biogenesis and increased oxidative stress in chondrocytes after TNF-α stimulation were mediated by PKR, which may contribute to the chondrocyte apoptosis and cartilage degeneration in OA.",
author = "Ma, {Ching Hou} and Wu, {Chin Hsien} and Jou, {I. Ming} and Tu, {Yuan Kun} and Hung, {Ching Hsia} and Chou, {Wan Ching} and Chang, {Yun Ching} and Hsieh, {Pei Ling} and Tsai, {Kun Ling}",
year = "2019",
month = "9",
doi = "10.3390/antiox8090370",
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PKR promotes oxidative stress and apoptosis of human articular chondrocytes by causing mitochondrial dysfunction through p38 MAPK activation—PKR activation causes apoptosis in human chondrocytes. / Ma, Ching Hou; Wu, Chin Hsien; Jou, I. Ming; Tu, Yuan Kun; Hung, Ching Hsia; Chou, Wan Ching; Chang, Yun Ching; Hsieh, Pei Ling; Tsai, Kun Ling.

In: Antioxidants, Vol. 8, No. 9, 370, 09.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PKR promotes oxidative stress and apoptosis of human articular chondrocytes by causing mitochondrial dysfunction through p38 MAPK activation—PKR activation causes apoptosis in human chondrocytes

AU - Ma, Ching Hou

AU - Wu, Chin Hsien

AU - Jou, I. Ming

AU - Tu, Yuan Kun

AU - Hung, Ching Hsia

AU - Chou, Wan Ching

AU - Chang, Yun Ching

AU - Hsieh, Pei Ling

AU - Tsai, Kun Ling

PY - 2019/9

Y1 - 2019/9

N2 - Osteoarthritis (OA) is one of the most common types of arthritis in the elderly people. It has been known that chondrocyte apoptosis occurs in OA cartilage; however, the detailed molecular mechanism remains unclear. In the current study, we aimed to elucidate the role of double-stranded RNA-dependent protein kinase R (PKR) in the TNF-α-caused apoptosis in chondrocytes. Human articular chondrocytes were digested from cartilages of OA subjects who accepted arthroplastic knee surgery. Our results showed that phosphorylation of p38 MAPK was increased after TNF-α stimulation or PKR activation using poly (I:C), and TNF-α-induced p38 MAPK upregulation was inhibited by PKR inhibition, suggesting phosphor-p38 MAPK was regulated by PKR. Moreover, we found that PKR participated in the p53-dependent destruction of AKT following activation of p38 MAPK. The inhibition of AKT led to the reduced expression of PGC-1α, which resulted in mitochondrial dysfunction and increased oxidative stress. We showed that the reduction of oxidative stress using antioxidant Mito TEMPO lowered the TNF-α-induced caspase-3 activation and TUNEL-positive apoptotic cells. The diminished apoptotic response was also observed after repression of PKR/p38 MAPK/p53/AKT/PGC-1α signaling. Taken together, we demonstrated that the aberrant mitochondrial biogenesis and increased oxidative stress in chondrocytes after TNF-α stimulation were mediated by PKR, which may contribute to the chondrocyte apoptosis and cartilage degeneration in OA.

AB - Osteoarthritis (OA) is one of the most common types of arthritis in the elderly people. It has been known that chondrocyte apoptosis occurs in OA cartilage; however, the detailed molecular mechanism remains unclear. In the current study, we aimed to elucidate the role of double-stranded RNA-dependent protein kinase R (PKR) in the TNF-α-caused apoptosis in chondrocytes. Human articular chondrocytes were digested from cartilages of OA subjects who accepted arthroplastic knee surgery. Our results showed that phosphorylation of p38 MAPK was increased after TNF-α stimulation or PKR activation using poly (I:C), and TNF-α-induced p38 MAPK upregulation was inhibited by PKR inhibition, suggesting phosphor-p38 MAPK was regulated by PKR. Moreover, we found that PKR participated in the p53-dependent destruction of AKT following activation of p38 MAPK. The inhibition of AKT led to the reduced expression of PGC-1α, which resulted in mitochondrial dysfunction and increased oxidative stress. We showed that the reduction of oxidative stress using antioxidant Mito TEMPO lowered the TNF-α-induced caspase-3 activation and TUNEL-positive apoptotic cells. The diminished apoptotic response was also observed after repression of PKR/p38 MAPK/p53/AKT/PGC-1α signaling. Taken together, we demonstrated that the aberrant mitochondrial biogenesis and increased oxidative stress in chondrocytes after TNF-α stimulation were mediated by PKR, which may contribute to the chondrocyte apoptosis and cartilage degeneration in OA.

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