title: Cynaropicrin is dual regulator for both degradation factors and synthesis factors in the cartilage metabolism.
abstract: OBJECTIVE
  The molecular mechanism of osteoarthritis (OA) has never been understood clearly, but it has been suggested that imbalance of degradation and synthesis in cartilage contribute to the underlying mechanisms of OA. In this study, we investigated the effectiveness in the cartilage metabolism of the artichoke extract that includes the compound cynaropicrin.
  
  
  METHODS
  We evaluated the efficacy of the artichoke extract or cynaropicrin in the cartilage metabolism factors and NF-κB signaling activity stimulated by inflammatory cytokine in chondrogenic cell lines, OUMS-27 and SW1353, using qRT-PCR, immunofluorescence and immunoblotting.
  
  
  RESULTS
  We initially found that an artichoke extract and cynaropicrin both inhibited the increase of cartilage degradation factor MMP13 and further decreased the synthesis factor aggrecan induced by TNF-α in OUMS-27. In addition, cynaropicrin suppressed the enhancement of master regulator HIF-2α on cartilage degradation and further reduced the master regulator Sox9 on cartilage synthesis induced by TNF-α. We observed that cynaropicrin suppresses NF-κB signaling, which controls HIF-2α and Sox9. Since, HIF-2α is induced by p65 (RelA), we evaluated the effect of cynaropicrin and observed that it suppressed the nuclear transport of p65 (RelA) by inhibiting phosphorylation of IκBα. Moreover, cynaropicrin not only suppressed TNF-α stimulation, it had a similar effect on IL-1β stimulation. No significant cytotoxicity with cynaropicrin was observed.
  
  
  CONCLUSIONS
  These finding suggest that cynaropicrin is an effective substance that can improve the balance of cartilage metabolism, by altering the equilibrium of cartilage degradation and synthesis induced by multiple mediators know to contribute to OA.
authors.affiliation: Medical Science Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan; Research & Development Dept., Ichimaru Pharcos Co., Ltd, 318-1 Asagi, Motosu City, Gifu 501-0475, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Masutani
authors.affiliation: Research & Development Dept., Ichimaru Pharcos Co., Ltd, 318-1 Asagi, Motosu City, Gifu 501-0475, Japan.
authors.forename: Yuka Tsuda
authors.initials: YT
authors.lastname: Tanaka
authors.affiliation: Research & Development Dept., Ichimaru Pharcos Co., Ltd, 318-1 Asagi, Motosu City, Gifu 501-0475, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Research & Development Dept., Ichimaru Pharcos Co., Ltd, 318-1 Asagi, Motosu City, Gifu 501-0475, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu City, Gifu 501-1194, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Medical Science Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan; Medical Development Center, Gifu University School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan. Electronic address: mniwa@gifu-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Niwa
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002356:Cartilage / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D006868:Hydrolysis; D007783:Lactones / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D053674:Aggrecans; D051792:Basic Helix-Loop-Helix Proteins; D007783:Lactones; D053509:Matrix Metalloproteinase 13; D016328:NF-kappa B; D055758:SOX9 Transcription Factor; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D000099162:Endothelial PAS Domain-Containing Protein 1; C527932:SOX9 protein, human; C507079:MMP13 protein, human; C075687:cynaropicrin
keywords: Cynaropicrin; Cynaropicrin (PubChem CID: 119093); HIF-2α; NF-κB; Osteoarthritis; Sox9