Suppression of Leukocyte Infiltration and Cartilage Degradation by Selective Inhibition of Pre B-Cell Colony-Enhancing Factor/Visfatin/Nicotinamide Phosphoribosyltransferase APO866-Mediated Therapy in Human Fibroblasts and Murine Collagen-Induced Arthritis
Suppression of Leukocyte Infiltration and Cartilage Degradation by Selective Inhibition of Pre B-Cell Colony-Enhancing Factor/Visfatin/Nicotinamide Phosphoribosyltransferase APO866-Mediated Therapy in Human Fibroblasts and Murine Collagen-Induced Arthritis
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DOI：
10.1002/art.30338
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发表时间：
2011-07-01
影响因子：
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通讯作者：
Nowell, Mari
中科院分区：
文献类型：
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作者：
Evans, Laura;Williams, Anwen S.;Nowell, Mari
Objective.为了评估前B细胞集落增强因子（PBEF）在炎症性关节炎中调节炎症和降解过程的能力，使用小分子抑制剂APO 866在体外人成纤维细胞和小鼠胶原诱导的关节炎（CIA）中。酶联免疫吸附试验用于检测人成纤维细胞中金属蛋白酶和趋化因子表达的调节。使用APO 866在CIA小鼠中进一步检查PBEF的作用，使用放射摄影、组织学、体内成像和定量聚合酶链反应（qPCR）评估对疾病活动的影响。体外用PBEF激活人成纤维细胞可促进基质金属蛋白酶3（MMP-3）、CCL 2和CXCL 8的表达，而APO 866可抑制这种作用。在CIA小鼠中，APO 866的早期干预抑制了滑膜炎症，包括趋化因子介导的白细胞浸润，并降低了炎症的全身标志物血清透明质酸。APO 866阻断导致关节提取物中MMP-3和MMP-13的表达减少，并导致软骨侵蚀的全身标志物血清软骨寡聚基质蛋白的减少。放射学图像显示，APO 866保护骨侵蚀，而qPCR显示RANKL表达的抑制。在患有疾病的小鼠中，APO 866减少了滑液炎症和软骨破坏，并阻止了骨侵蚀。此外，APO 866降低了体内MMP-3、CCL 2和RANKL的活性，并抑制关节炎小鼠滑膜外植体中CCL 2和RANKL的产生，这一结果被烟酰胺单核苷酸肽逆转。这些发现证实PBEF是炎症、软骨炎和骨侵蚀的重要调节剂，并强调APO 866是一种有前途的治疗剂，用于靶向炎症性关节炎中的PBEF活性。
Objective. To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collagen-induced arthritis (CIA).Methods. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).Results. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radio logic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.Conclusion. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.