title: Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation.
abstract: Advanced oxidation protein products (AOPPs) are recognized as novel markers of oxidative stress and contribute to various medical conditions, which are associated with secondary osteoporosis. However, little is currently known regarding the role of AOPPs in the development of secondary osteoporosis. As the commander cells of bone remodeling, osteocytes are involved in the pathogenesis of osteoporosis. The present study aimed to determine the cytotoxic mechanisms of AOPPs on osteocytic MLO‑Y4 cells. The results demonstrated that treatment with AOPPs significantly triggered apoptosis of MLO‑Y4 cells, in a dose‑ and time‑dependent manner. Furthermore, exposure to AOPPs induced phosphorylation of c‑Jun N‑terminal kinases (JNK) and p38 mitogen‑activated protein kinases (MAPK). Conversely, N‑acetylcysteine inhibited the activation of JNK and p38 MAPK, thus suggesting that the AOPPs‑induced activation of JNK/p38 MAPK is reactive oxygen species (ROS)‑dependent. In addition, SB203580 and SP600125 suppressed apoptosis, but did not affect ROS production, following AOPPs treatment. Notably, AOPPs also induced a significant upregulation in the expression levels of sclerostin and receptor activator of nuclear factor kappa‑B ligand (RANKL) in a JNK/p38 MAPK-dependent manner. These findings provide novel insights into the molecular mechanisms underlying AOPPs‑mediated cell death, and suggest that modulation of apoptotic pathways via the MAPK signaling cascade may be considered a therapeutic strategy for the prevention and treatment of secondary osteoporosis.
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Nephrology, The First Clinical College, Southern Medical University, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Kunyuan
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Bochuan
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Yuanhang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Songbo
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Weichi
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Traumatology and Microsurgery, The Third Clinical College, Southern Medical University, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510310, P.R. China.
authors.forename: Huiru
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D062107:Advanced Oxidation Protein Products / Q000633:toxicity*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D062107:Advanced Oxidation Protein Products; D000873:Anthracenes; D006023:Glycoproteins; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D011725:Pyridines; D053245:RANK Ligand; D017382:Reactive Oxygen Species; C486030:Sost protein, mouse; C432165:pyrazolanthrone; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000111:Acetylcysteine