title: A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis.
abstract: An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress-associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1β, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of Grp78 transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-β-induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the Grp78 gene prevented synoviocyte apoptosis. Moreover, Grp78 small interfering RNA inhibited VEGF(165)-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with Grp78 haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA.
authors.affiliation: Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.forename: Sungyong
authors.initials: S
authors.lastname: You
authors.forename: Hyung-Ju
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Kim
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Kyungho
authors.initials: K
authors.lastname: Lee
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: Ki-Jo
authors.initials: KJ
authors.lastname: Kim
authors.forename: Yune-Jung
authors.initials: YJ
authors.lastname: Park
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D000328:Adult; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology*; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D010003:Osteoarthritis / Q000209:etiology; D013861:Thiocyanates / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: C527742:1-(3,4-dihydroxyphenyl)-2-thiocyanate-ethanone; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D013861:Thiocyanates; D042461:Vascular Endothelial Growth Factor A