title: Necessity of lysophosphatidic acid receptor 1 for development of arthritis.
abstract: OBJECTIVE
  Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA1 on the development of arthritis.
  
  
  METHODS
  Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA1 on collagen-induced arthritis (CIA) were evaluated using LPA1 -deficient mice or LPA1 antagonist. Migrating fluorescence-labeled CD11b+ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4+ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.
  
  
  RESULTS
  LPA1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA1 antagonist also ameliorated murine CIA. Abrogation of LPA1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b+ macrophages from LPA1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA1 deficiency or LPA1 inhibition in vitro.
  
  
  CONCLUSIONS
  Collectively, these results indicate that LPA/LPA1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA1 may be a promising target molecule for RA therapy.
authors.affiliation: Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Miyabe
authors.forename: Chie
authors.initials: C
authors.lastname: Miyabe
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwai
authors.forename: Aiko
authors.initials: A
authors.lastname: Takayasu
authors.forename: Shin
authors.initials: S
authors.lastname: Fukuda
authors.forename: Waka
authors.initials: W
authors.lastname: Yokoyama
authors.forename: Jun
authors.initials: J
authors.lastname: Nagai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Jona
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tokuhara
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Ohkawa
authors.forename: Harald M
authors.initials: HM
authors.lastname: Albers
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
mesh_terms: D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen; D002454:Cell Differentiation; D017690:Cell Transplantation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells
chemical_list: D039481:CD11b Antigen; D049368:Receptors, Lysophosphatidic Acid