THU0106 Lysophosphatidic Acid Receptor LPA1 is Essential for Development of Arthritis

Background Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA 1-6 ) and has been implicated as an important mediator of angiogenesis, inflammation and cancer growth [1-3]. Objectives To explore the pathogenic roles of LPA 1 on rheumatoid arthritis, we examined the effects of LPA 1 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 LPA 1 on collagen-induced arthritis (CIA) was evaluated using LPA 1 -deficient mice or LPA 1 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 + naive 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 LPA 1 was highly expressed in the synovium of rheumatoid arthritis (RA) compared to osteoarthritis. LPA 1 -deficient mice failed to develop arthritis following collagen type-II (CII) immunization. LPA 1 antagonist ameliorated murine CIA. Abrogation of LPA 1 was associated with reduced cell infiltrates, bone destruction in the joints, and IL-17 production from CII-stimulated splenocytes. Infiltration of transferred LPA 1 -deficient CD11b + macrophages into the synovium was suppressed compared with wild-type macrophages. LPA 1 antagonist inhibited the infiltration of wild-type macrophages. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed in LPA 1 -deficienct mice or LPA 1 inhibition in vitro . Conclusions LPA-LPA 1 signaling critically contributes to the development of arthritis by cellular infiltration, Th17 differentiation and osteoclastogenesis, suggesting that LPA 1 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