A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis
A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis
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DOI：
10.1111/bph.12768
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发表时间：
2014-09-01
影响因子：
7.3
通讯作者：
Yang, Y. H.
中科院分区：
文献类型：
--
作者：
Kao, W.;Gu, R.;Yang, Y. H.
背景和目的膜联蛋白 A1 (AnxA1) 是一种内源性抗炎蛋白，也是甲酰肽受体 2 (FPR2) 的激动剂。然而，治疗性 FPR 配体改变免疫介导疾病的潜力尚未被探索。我们在类风湿性关节炎 (RA) 和 RA 成纤维细胞样滑膜细胞 (FLS) 的 K/BxN 模型中研究了合成 FPR 激动剂对关节疾病的影响。实验方法在第 0 天和第 2 天向野生型 (WT) 或 AnxA1(-/-) 小鼠注射 K/BxN 血清诱导关节炎，并在 8-11 天后测量临床和组织病理学表现。 WT 小鼠腹腔注射 FPR 激动剂化合物 43 (Cpd43)（6 或 30 mg kg(-1)）4 天。在 RAW 264.7 细胞、人 RA FLS 和巨噬细胞中评估了 AnxA1 和 Cpd43 对 RANKL 诱导的破骨细胞生成的影响。 关键结果 在关节炎发作之前或之后使用 Cpd43 治疗可减轻临床疾病的严重程度，并减弱滑膜 TNF-α 和破骨细胞相关基因的表达。在 K/BxN 模型中，小鼠 AnxA1 的缺失加剧了关节炎的严重程度。在体外，Cpd43 抑制破骨细胞生成和 RANKL 引发的 NFAT 活性，并抑制小鼠巨噬细胞分泌 IL-6。在人 RA 关节来源的 FLS 和单核细胞来源的巨噬细胞中，Cpd43 治疗抑制 IL-6 释放，而阻断 FPR2 或沉默 AnxA1 则增加这种释放。 结论和意义 FPR 激动剂 Cpd43 减少 RA 小鼠模型中的破骨细胞生成和炎症，并在相关人类细胞中表现出抗炎作用。这些数据表明，FPR 配体可能代表能够改善 RA 炎症和骨损伤的新型治疗剂。
BACKGROUND AND PURPOSEAnnexin A1 (AnxA1) is an endogenous anti-inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast-like synoviocytes (FLS).EXPERIMENTAL APPROACHArthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type (WT) or AnxA1(-/-) mice and clinical and histopathological manifestations measured 8-11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg kg(-1) i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL-induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages.KEY RESULTSTreatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF-alpha and osteoclast-associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 increased this release.CONCLUSIONS AND IMPLICATIONSThe FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA.