title: Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis.
abstract: BACKGROUND
  Osteoarthritis (OA) is a common joint disease that can cause gradual disability among the aging population. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor that regulates the expression of phase II antioxidant enzymes that provide protection against oxidative stress and tissue damage. The use of histone deacetylase inhibitors (HDACi) has emerged as a potential therapeutic strategy for various diseases. They have displayed chondroprotective effects in various animal models of arthritis. Previous studies have established that Nrf2 acetylation enhances Nrf2 functions. Here we explore the role of Nrf2 in the development of OA and the involvement of Nrf2 acetylation in HDACi protection of OA.
  
  
  METHODS
  Two OA models-monosodium iodoacetate (MIA) articular injection and destabilization of the medial meniscus (DMM)-were used with wild-type (WT) and Nrf2-knockout (Nrf2-KO) mice to demonstrate the role of Nrf2 in OA progression. A pan-HDACi, trichostatin A (TSA), was administered to examine the effectiveness of HDACi on protection from cartilage damage. The histological sections were scored. The expression of OA-associated matrix metalloproteinases (MMPs) 1, 3, and 13 and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were assayed. The effectiveness of HDACi on OA protection was compared between WT and Nrf2-KO mice.
  
  
  RESULTS
  Nrf2-KO mice displayed more severe cartilage damage in both the MIA and DMM models. TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the expression of OA-associated proteins MMP1, MMP3, and MMP13 and proinflammatory cytokines TNF-α, IL-1β, and IL-6. TSA markedly reduced the cartilage damage in both OA models but offered no significant protection in Nrf2-KO mice.
  
  
  CONCLUSIONS
  Nrf2 has a major chondroprotective role in progression of OA and is a critical molecule in HDACi-mediated OA protection.
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, People's Republic of China. 850565332@qq.com.|Center of Diagnosis and Treatment for Joint Disease, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, 210008, People's Republic of China. 850565332@qq.com.
authors.forename: Dawei
authors.initials: D
authors.lastname: Cai
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, People's Republic of China. sswwyql@163.com.
authors.forename: Shasha
authors.initials: S
authors.lastname: Yin
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, People's Republic of China. yangjuni0704@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, People's Republic of China. qingj@nju.edu.cn.|Center of Diagnosis and Treatment for Joint Disease, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, 210008, People's Republic of China. qingj@nju.edu.cn.|Model Animal Research Center of Nanjing University, Nanjing, 210032, People's Republic of China. qingj@nju.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, People's Republic of China. wangsencao@nju.edu.cn.|National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, People's Republic of China. wangsencao@nju.edu.cn.
authors.forename: Wangsen
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C012589:trichostatin A