Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis. Issue 8 (26th July 2013)

• Record Type: Journal Article
• Authors: Miyabe, Yoshishige; Miyabe, Chie; Iwai, Yoshiko; Takayasu, Aiko; Fukuda, Shin; Yokoyama, Waka; Nagai, Jun; Jona, Masahiro; Tokuhara, Yasunori; Ohkawa, Ryunosuke; Albers, Harald M.; Ovaa, Huib; Aoki, Junken; Chun, Jerold; Yatomi, Yutaka; Ueda, Hiroshi; Miyasaka, Masayuki; Miyasaka, Nobuyuki; Nanki, Toshihiro
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 8(2013:Aug.)
• Page Start: 2037
• Page End: 2047
• Publication Date: 2013-07-26
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37991
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art37991-sec-0001" sec-type="section"> <title>Objective</title> <p>Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein–coupled receptors (LPA receptors 1–6 [LPA<sub>1–6</sub>]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA<sub>1</sub> on the development of arthritis.</p> </sec> <sec id="art37991-sec-0002" sec-type="section"> <title>Methods</title> <p>Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription–polymerase chain reaction. The effects of abrogation of LPA<sub>1</sub> on collagen‐induced arthritis (CIA) were evaluated using LPA<sub>1</sub>‐deficient mice or LPA<sub>1</sub> 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.</p> </sec> <sec id="art37991-sec-0003" sec-type="section"> <title>Results</title> <p>LPA<sub>1</sub> was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA<sub>1</sub>‐deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA<sub>1</sub> antagonist also ameliorated murine CIA. Abrogation of LPA<sub>1</sub> 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 LPA<sub>1</sub>‐deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild‐type mice. LPA<sub>1</sub> 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 LPA<sub>1</sub> deficiency or LPA<sub>1</sub> inhibition in vitro.</p> </sec> <sec id="art37991-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Collectively, these results indicate that LPA/LPA<sub>1</sub> signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA<sub>1</sub> may be a promising target molecule for RA therapy.</p> </sec> </abstract>