title: Folate Deficiency Triggered Apoptosis of Synoviocytes: Role of Overproduction of Reactive Oxygen Species Generated via NADPH Oxidase/Mitochondrial Complex II and Calcium Perturbation.
abstract: Despite a plethora of literature has documented that osteoarthritis (OA) is veritably associated with oxidative stress-mediated chondrocyte death and matrix degradation, yet the possible involvement of synoviocyte abnormality as causative factor of OA has not been thoroughly investigated. For this reason, we conduct the current studies to insight into how synoviocytes could respond to an episode of folate-deprived (FD) condition. First, when HIG-82 synoviocytes were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature mediated through FD-evoked overproduction of reactive oxygen species (ROS) and drastically released of cytosolic calcium (Ca2+) concentrations. Next, we uncovered that FD-evoked ROS overproduction could only be strongly suppressed by either mitochondrial complex II inhibitors (TTFA and carboxin) or NADPH oxidase (NOX) inhibitors (AEBSF and apocynin), but not by mitochondrial complex I inhibitor (rotenone) and mitochondrial complex III inhibitor (antimycin A). Interestingly, this selective inhibition of FD-evoked ROS by mitochondrial complex II and NOX inhibitors was found to correlate excellently with the suppression of cytosolic Ca2+ release and reduced the magnitude of the apoptotic TUNEL-positive cells. Taken together, we present the first evidence here that FD-triggered ROS overproduction in synoviocytes is originated from mitochondrial complex II and NOX. Both elevated ROS in tandem with cytosolic Ca2+ overload serve as final arbitrators for apoptotic lethality of synoviocytes cultivated under FD condition. Thus, folate supplementation may be beneficial to patients with OA.
authors.affiliation: Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan.|Department of Nursing, Chang-Gung University of Science and Technology, Chia-Yi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Center of Advanced Integrative Sports Medicine, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Hsu
authors.affiliation: Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan.|Department of Nursing, Chang-Gung University of Science and Technology, Chia-Yi, Taiwan.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Chang
authors.affiliation: Department of Microbiology, Immunology and Biopharmaceuticals, Collage of Life Sciences, National Chiayi University, Chiayi City 60004, Taiwan.
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Immunology and Biopharmaceuticals, Collage of Life Sciences, National Chiayi University, Chiayi City 60004, Taiwan.
authors.forename: Chin-Chin
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Fung-Jou
authors.initials: FJ
authors.lastname: Lu
authors.affiliation: Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan.|Department of Nursing, Chang-Gung University of Science and Technology, Chia-Yi, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chuang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Pey-Jium
authors.initials: PJ
authors.lastname: Chang
authors.affiliation: Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan.|Department of Nursing, Chang-Gung University of Science and Technology, Chia-Yi, Taiwan.
authors.forename: Kai-Hua
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Department of Physical therapy, Hung Kuang University, Taichung, Taiwan.
authors.forename: Chang-Zern
authors.initials: CZ
authors.lastname: Hong
authors.affiliation: Department of Physical Medicine and Rehabilitation, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan.
authors.forename: Rang-Hui
authors.initials: RH
authors.lastname: Yeh
authors.affiliation: Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan.
authors.forename: Tsan-Zon
authors.initials: TZ
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology and Biopharmaceuticals, Collage of Life Sciences, National Chiayi University, Chiayi City 60004, Taiwan.
authors.forename: Ching-Hsein
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002261:Carboxin / Q000494:pharmacology; D002460:Cell Line; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000502:physiology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D013450:Sulfones; D012402:Rotenone; D013804:Thenoyltrifluoroacetone; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D002261:Carboxin; D005492:Folic Acid; D042963:Electron Transport Complex II; D019255:NADPH Oxidases; D002118:Calcium