title: Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction.
abstract: OBJECTIVE
  The basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA).
  
  
  METHODS
  Primary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1β, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad-Batf). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad-Batf. The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes.
  
  
  RESULTS
  Overexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice.
  
  
  CONCLUSIONS
  BATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jinseol
authors.initials: J
authors.lastname: Rhee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: Park
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.|School of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul, Korea.
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, SungKyunKwan University School of Medicine, Seoul, Korea.|Department of Health Sciences and Technology, SAIHST, SungKyunKwan University, Seoul, South Korea.
authors.forename: Chul-Won
authors.initials: CW
authors.lastname: Ha
authors.affiliation: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan, Korea.
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C099359:BATF protein, human; D050976:Basic-Leucine Zipper Transcription Factors; C431772:Batf protein, mouse; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha
keywords: Chondrocytes; Cytokines; Osteoarthritis