title: Dysregulated osteoclastogenesis is related to natural killer T cell dysfunction in rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction.
  
  
  METHODS
  Patients with rheumatoid arthritis (RA) (n = 25) and healthy controls (n = 12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of macrophage colony-stimulating factor and RANKL. PBMCs were cultured in vitro with α-galactosylceramide (αGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of αGalCer-stimulated NKT cells on inflammation and bone destruction were determined in mice with collagen-induced arthritis.
  
  
  RESULTS
  In vitro osteoclastogenesis was found to be significantly inhibited by αGalCer in healthy controls but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to αGalCer were impaired in RA patients. Notably, αGalCer-stimulated NKT cells inhibited osteoclastogenesis mainly via interferon-γ production in a cytokine-dependent manner (not by cell-cell contact) and down-regulated osteoclast-associated genes. Mice treated with αGalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by αGalCer treatment.
  
  
  CONCLUSIONS
  This study primarily demonstrates that αGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect against inflammatory bone destruction. However, it also shows that these effects of αGalCer are diminished in RA patients and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA.
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Jin
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Seung-Jung
authors.initials: SJ
authors.lastname: Kee
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Young-Nan
authors.initials: YN
authors.lastname: Cho
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Moon-Ju
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Ki-Jeong
authors.initials: KJ
authors.lastname: Park
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Tae-Jong
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Gyeongsang National University School of Medicine, Gyeongnam, Republic of Korea.
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Lee
authors.affiliation: Chonnam National University School of Dentistry, Gwangju, Republic of Korea.
authors.forename: Hyuck
authors.initials: H
authors.lastname: Choi
authors.affiliation: Chonnam National University School of Dentistry, Gwangju, Republic of Korea.
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Koh
authors.affiliation: Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
authors.affiliation: Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea.
authors.forename: Yong-Wook
authors.initials: YW
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010000:Osteitis / Q000473:pathology / Q000503:physiopathology*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D005699:Galactosylceramides; D050794:STAT1 Transcription Factor; C493154:alpha-galactosylceramide; D007371:Interferon-gamma