title: Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes.
abstract: Osteoarthritis (OA), characterized by progressive destruction of articular cartilage, is the most common form of human arthritis. Here, we evaluated the potential chondroprotective and anti-inflammatory effects of Wogonin, a naturally occurring flavonoid, in IL-1β-stimulated human OA chondrocytes and cartilage explants. Wogonin completely suppressed the expression and production of inflammatory mediators including IL-6, COX-2, PGE2, iNOS and NO in IL-1β-stimulated OA chondrocytes. Further, Wogonin exhibits potent chondroprotective potential by switching the signaling axis of matrix degradation from catabolic towards anabolic ends and inhibited the expression, production and activities of matrix degrading proteases including MMP-13, MMP-3, MMP-9, and ADAMTS-4 in OA chondrocytes, and blocked the release of s-GAG and COL2A1 in IL-1β-stimulated OA cartilage explants. Wogonin also elevated the expression of cartilage anabolic factors COL2A1 and ACAN in chondrocytes and inhibited the IL-1β-mediated depletion of COL2A1 and proteoglycan content in the matrix of cartilage explants. The suppressive effect of Wogonin was not mediated through the inhibition of MAPKs or NF-κB activation. Instead, Wogonin induced mild oxidative stress through the generation of ROS and depletion of cellular GSH, thereby modulating the cellular redox leading to the induction of Nrf2/ARE pathways through activation of ROS/ERK/Nrf2/HO-1-SOD2-NQO1-GCLC signaling axis in OA chondrocytes. Molecular docking studies revealed that Wogonin can disrupt KEAP-1/Nrf-2 interaction by directly blocking the binding site of Nrf-2 in the KEAP-1 protein. Genetic ablation of Nrf2 using specific siRNA, significantly abrogated the anti-inflammatory and chondroprotective potential of Wogonin in IL-1β-stimulated OA chondrocytes. Our data indicates that Wogonin exerts chondroprotective effects through the suppression of molecular events involved in oxidative stress, inflammation and matrix degradation in OA chondrocytes and cartilage explants. The study provides novel insights into the development of Nrf2 as a promising candidate and Wogonin as a therapeutic agent for the management of OA.
authors.affiliation: Department of Anatomy & Neurobiology, Northeast Ohio Medical University, 4209 St Rt 44, Rootstown, OH 44272, USA.
authors.forename: Nazir M
authors.initials: NM
authors.lastname: Khan
authors.affiliation: Department of Anatomy & Neurobiology, Northeast Ohio Medical University, 4209 St Rt 44, Rootstown, OH 44272, USA.
authors.forename: Abdul
authors.initials: A
authors.lastname: Haseeb
authors.affiliation: Department of Anatomy & Neurobiology, Northeast Ohio Medical University, 4209 St Rt 44, Rootstown, OH 44272, USA.
authors.forename: Mohammad Y
authors.initials: MY
authors.lastname: Ansari
authors.affiliation: Department of Anatomy & Neurobiology, Northeast Ohio Medical University, 4209 St Rt 44, Rootstown, OH 44272, USA.
authors.forename: Pratap
authors.initials: P
authors.lastname: Devarapalli
authors.affiliation: Department of Anatomy & Neurobiology, Northeast Ohio Medical University, 4209 St Rt 44, Rootstown, OH 44272, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Haynie
authors.affiliation: Department of Anatomy & Neurobiology, Northeast Ohio Medical University, 4209 St Rt 44, Rootstown, OH 44272, USA. Electronic address: thaqqi@neomed.edu.
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Haqqi
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D044950:Flavanones / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D062105:Molecular Docking Simulation; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D044950:Flavanones; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C085514:wogonin
keywords: ERK1/2; Nrf2; Osteoarthritis; Redox; Wogonin