title: Epigallocatechin-3-gallate diminishes cytokine-stimulated Cyr61 expression in human osteoblastic cells: a therapeutic potential for arthritis.
abstract: OBJECTIVE
  To assess the effects of epigallocatechin-3-gallate (EGCG) on cytokine-induced Cyr61 synthesis in human osteoblastic cells and the associated signalling pathways. The therapeutic effect of EGCG on CIA in rats was also studied.
  
  
  METHODS
  The expression of Cyr61 and NF-κB pathway molecules was examined by western blotting. CCL2 expression was assessed by northern blotting and ELISA. Interaction between NF-κB and Cyr61 promoter was evaluated by electrophoretic mobility shift assay. In rat CIA, osteoblastic expression of Cyr61 was examined by immunohistochemistry and disease progression was assessed by clinical, radiographic and histological examinations.
  
  
  RESULTS
  EGCG inhibited Cyr61 expression stimulated by cytokines in primary human osteoblasts and human osteoblastic cell line U2OS. In U2OS, oncostatin M (OSM) induced IκB-α degradation through the mTOR/rictor/Akt pathway, and EGCG attenuated the action. Electrophoretic mobility shift assay revealed that the OSM-enhanced NF-κB/DNA binding was reduced by EGCG, possibly through abrogating nucleus localization of p65 and p50. Cyr61 enhanced OSM-induced expression of CCL2. Moreover, EGCG diminished OSM-stimulated CCL2 expression at least partially via suppressing Cyr61 induction. Co-distribution of CD68(+) macrophages and Cyr61(+) osteoblasts in osteolytic areas was obvious in the CIA model. Clinical, radiographic and immunohistochemical analyses revealed that administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the number of Cyr61-synthesizing osteoblasts.
  
  
  CONCLUSIONS
  By modulating the mTOR/rictor/Akt/NF-κB pathway, EGCG attenuated Cyr61 production in osteoblastic cells and in turn diminished macrophage chemotaxis. Our data support the therapeutic potential of EGCG on arthritis.
authors: Department of Dentistry, School of Dentistry, National Taiwan University, No. 1, Chang-Te Street, Taipei 10016, Taiwan. prospect.dental@gmail.com
authors: Ping-Han
authors: PH
authors: Wu
authors: Sze-Kwan
authors: SK
authors: Lin
authors: Bor-Shiunn
authors: BS
authors: Lee
authors: Sang-Heng
authors: SH
authors: Kok
authors: Jyh-Horng
authors: JH
authors: Wang
authors: Kuo-Liang
authors: KL
authors: Hou
authors: Hsiang
authors: H
authors: Yang
authors: Eddie Hsiang-Hua
authors: EH
authors: Lai
authors: Juo-Song
authors: JS
authors: Wang
authors: Chi-Yuan
authors: CY
authors: Hong
mesh_terms: D000328:Adult; D000818:Animals; D001168:Arthritis / Q000378:metabolism / Q000628:therapy*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D055515:Cysteine-Rich Protein 61 / Q000096:biosynthesis* / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: C435044:1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol; D018932:Chemokine CCL2; D002867:Chromones; D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D009025:Morpholines; D016328:NF-kappa B; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002392:Catechin; C045651:epigallocatechin gallate; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus