title: Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway.
abstract: Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Zhao-Ming
authors.initials: ZM
authors.lastname: Zhong
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Si-Yuan
authors.initials: SY
authors.lastname: Zhu
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Cong-Rui
authors.initials: CR
authors.lastname: Liao
authors.affiliation: Department of Oncology, Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Orthopedics, Jiangxi Provincial People's Hospital, Nanchang, China.
authors.forename: Ji-Huan
authors.initials: JH
authors.lastname: Zeng
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Ruo-Ting
authors.initials: RT
authors.lastname: Ding
authors.affiliation: Department of Orthopedics, Shekou People's Hospital, Shenzhen, China.
authors.forename: Qing-Song
authors.initials: QS
authors.lastname: Lin
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Ye
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China. chenjt99@tom.com.
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Chen
mesh_terms: D062107:Advanced Oxidation Protein Products / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D062107:Advanced Oxidation Protein Products; C000593874:Ager protein, rat; D018955:CD36 Antigens; C008132:Cd36 protein, rat; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D019255:NADPH Oxidases
keywords: Advanced oxidation protein products; Apoptosis; Intrinsic apoptosis pathway; Nicotinamide adenine dinucleotide phosphate oxidase; Rat chondrocyte; Reactive oxygen species