title: Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis.
abstract: OBJECTIVE
  Calcineurin-binding protein 1 (CABIN-1) regulates calcineurin phosphatase activity as well as the activation, apoptosis, and inflammatory responses of fibroblast-like synoviocytes (FLS), which actively participate in the chronic inflammatory responses in rheumatoid arthritis (RA). However, the mechanism of action of CABIN-1 in FLS apoptosis is not clear. This study was undertaken to define the regulatory role of CABIN-1 in FLS from mice with collagen-induced arthritis (CIA).
  
  
  METHODS
  Transgenic mice overexpressing human CABIN-1 in joint tissue under the control of a type II collagen promoter were generated. Expression of human CABIN-1 (hCABIN-1) in joints and FLS was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of cytokines, matrix metalloproteinases (MMPs), and apoptosis-related genes in FLS was determined by enzyme-linked immunosorbent assay, gelatin zymography, and RT-PCR, respectively. Joints were stained with hematoxylin and eosin and with tartrate-resistant acid phosphatase for histologic analysis.
  
  
  RESULTS
  Human CABIN-1-transgenic mice with CIA had less severe arthritis than wild-type mice with CIA, as assessed according to hind paw thickness and histologic features. The milder arthritis was accompanied by significantly enhanced apoptosis in transgenic mice, evidenced by a significantly greater number of TUNEL-positive cells in synovial tissue. Expression of inflammatory cytokines and MMPs in the transgenic mice with CIA was reduced, and they exhibited decreased Akt activation and increased expression of p53, caspase 3, caspase 9, and Bax.
  
  
  CONCLUSIONS
  Our findings demonstrate that hCABIN-1 plays a critical role in promoting apoptosis of FLS and in attenuating inflammation and cartilage and bone destruction in RA. These results help elucidate the pathogenic mechanisms of RA and suggest that CABIN-1 is a potential target for treatment of this disease.
authors.affiliation: Kyungpook National University, Daegu, South Korea.
authors.forename: Jun-Koo
authors.initials: JK
authors.lastname: Yi
authors.forename: Hei-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Yu
authors.forename: Seo-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Shin
authors.forename: Hyung-Soo
authors.initials: HS
authors.lastname: Yuh
authors.forename: Ki-Beom
authors.initials: KB
authors.lastname: Bae
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Ji
authors.forename: Na-Ri
authors.initials: NR
authors.lastname: Kim
authors.forename: Si-Jun
authors.initials: SJ
authors.lastname: Park
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.forename: Sang-Gyu
authors.initials: SG
authors.lastname: Lee
authors.forename: Du Hak
authors.initials: du H
authors.lastname: Yoon
authors.forename: Byung-Hwa
authors.initials: BH
authors.lastname: Hyun
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
authors.forename: Zae-Young
authors.initials: ZY
authors.lastname: Ryoo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D020782:Matrix Metalloproteinases