Folate deficiency triggered apoptosis of synoviocytes: Role of overproduction of reactive oxygen species generated via NADPH oxidase/mitochondrial complex II and Calcium Perturbation

Hung Chih Hsu, Wen Ming Chang, Jin Yi Wu, Chin Chin Huang, Fung Jou Lu, Yi Wen Chuang, Pey Jium Chang, Kai Hua Chen, Chang Zern Hong, Rang Hui Yeh, Tsan Zon Liu, Ching Hsein Chen

Research output: Contribution to journalJournal Article peer-review

17 Scopus citations

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.

Original languageEnglish
Article numbere0146440
JournalPLoS ONE
Volume11
Issue number1
DOIs
StatePublished - 01 01 2016

Bibliographical note

Publisher Copyright:
© 2016 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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