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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

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-dependen...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769915/
https://www.ncbi.nlm.nih.gov/pubmed/31484360
http://dx.doi.org/10.3390/antiox8090370
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author 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
author_facet 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
author_sort Ma, Ching-Hou
collection PubMed
description 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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spelling pubmed-67699152019-10-30 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 Antioxidants (Basel) Article 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. MDPI 2019-09-03 /pmc/articles/PMC6769915/ /pubmed/31484360 http://dx.doi.org/10.3390/antiox8090370 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769915/
https://www.ncbi.nlm.nih.gov/pubmed/31484360
http://dx.doi.org/10.3390/antiox8090370
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