Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis
Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis
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DOI：
10.1002/art.37991
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发表时间：
2013-08-01
影响因子：
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通讯作者：
Nanki, Toshihiro
中科院分区：
文献类型：
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作者：
Miyabe, Yoshishige;Miyabe, Chie;Nanki, Toshihiro
Objective.溶血磷脂酸（LPA）是一种生物活性脂质，其与一组细胞表面G蛋白偶联受体（LPA受体1-6 [LPA（1-6）]）结合，并被认为是血管生成、炎症和癌症生长的重要介质。本研究旨在分析LPA（1）在关节炎发生发展中的作用。通过免疫组化和定量逆转录聚合酶链反应分析滑膜组织中LPA受体的表达。使用LPA（1）缺陷小鼠或LPA（1）拮抗剂评价LPA（1）废除对胶原诱导的关节炎（CIA）的影响。对转移到CIA小鼠滑膜中的迁移荧光标记的CD 11b+脾细胞进行计数。将CD 4+初始T细胞在Th 1-、Th 2-或Th 17-极化条件下孵育，并评估T辅助细胞分化。检测骨髓细胞破骨细胞形成。LPA（1）在类风湿关节炎（RA）患者滑膜中的表达高于骨关节炎患者。LPA（1）缺陷小鼠在用II型胶原（CII）免疫后没有发生关节炎。LPA（1）拮抗剂也能改善小鼠CIA。LPA（1）的消除与细胞浸润、关节骨破坏以及CII刺激的脾细胞产生的白细胞介素-17的减少有关。与野生型小鼠的巨噬细胞浸润相比，LPA（1）缺陷小鼠转移的CD 11b+巨噬细胞向滑膜的浸润受到抑制。LPA（1）拮抗剂可抑制野生型小鼠巨噬细胞的浸润。在体外实验中，LPA（1）缺乏或LPA（1）抑制均可抑制细胞向Th 17细胞分化，但对Th 1或Th 2细胞的分化无影响，并抑制破骨细胞的形成。总的来说，这些结果表明LPA/LPA（1）信号通过细胞浸润、Th 17分化和破骨细胞生成促进关节炎的发展。因此，LPA（1）可能是RA治疗的一个有希望的靶分子。
Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA(1-6)]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA(1) 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 LPA(1) on collagen-induced arthritis (CIA) were evaluated using LPA(1)-deficient mice or LPA(1) 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. LPA(1) was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA(1)-deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA(1) antagonist also ameliorated murine CIA. Abrogation of LPA(1) 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(1)-deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA(1) 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(1) deficiency or LPA(1) inhibition in vitro.Conclusion. Collectively, these results indicate that LPA/LPA(1) signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA(1) may be a promising target molecule for RA therapy.