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.
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Disclosure of Interest None Declared