THU0106 Lysophosphatidic Acid Receptor LPA1 is Essential for Development of Arthritis. (23rd January 2014)

• Record Type: Journal Article
• Authors: Miyabe, Y.; Miyabe, C.; Iwai, Y.; Takayasu, A.; Fukuda, S.; Yokoyama, W.; Nagai, J.; Jona, M.; Tokuhara, Y.; Ohkawa, R.; Albers, H. M.; Ovaa, H.; Aoki, J.; Chun, J.; Yatomi, Y.; Ueda, H.; Miyasaka, M.; Miyasaka, N.; Nanki, T.
• Is Part Of: Annals of the rheumatic diseases. Volume 72:Supplement 3(2013)
• Page Start: A198
• Page End: A198
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-eular.634
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA1-6 ) and has been implicated as an important mediator of angiogenesis, inflammation and cancer growth [1 -3 ]. Objectives: To explore the pathogenic roles of LPA1 on rheumatoid arthritis, we examined the effects of LPA1 on immune function and development of arthritis. Methods: Expression of LPA receptors on the synovial tissue was analyzed by immunohistochemistry and quantitative RT-PCR. Effect of abrogation of LPA1 on collagen-induced arthritis (CIA) was evaluated using LPA1 -deficient mice or LPA1 antagonist. Fluorescence labeled-CD11b + splenocytes were transferred into CIA mice. Twenty-four hours after the transfer, the numbers of labeled cells in the synovium were counted under fluorescent microscopy. CD4 + naïve T cells were incubated with T helper (Th)1-, Th2-, or Th17-polarizing conditions and Th differentiation was analyzed. Osteoclast formation from bone marrow cells was examined. Results: LPA1 was highly expressed in the synovium of rheumatoid arthritis (RA) compared to osteoarthritis. LPA1 -deficient mice failed to develop arthritis following collagen type-II (CII) immunization. LPA1 antagonist ameliorated murine CIA. Abrogation of LPA1 was associated with reduced cell infiltrates, bone destruction in the joints, and IL-17 production from CII-stimulated splenocytes. Infiltration of transferred LPA1 -deficient CD11b + macrophages into the synovium was suppressed compared with wild-type macrophages. LPA1 antagonist inhibited the infiltration of wild-type macrophages. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed in LPA1 -deficienct mice or LPA1 inhibition in vitro . Conclusions: LPA-LPA1 signaling critically contributes to the development of arthritis by cellular infiltration, Th17 differentiation and osteoclastogenesis, suggesting that LPA1 is a promising target molecule for RA therapy. References: Schleicher SM, et al. PLoS One. 2011; 6: e22182. Xu X, et al. Cancer. 2010; 116: 1739-1750. Houben AJ, et al. Cancer Metastasis Rev. 2011; 30: 557-565. Disclosure of Interest: None Declared