Bar-Yehuda S, Rath-Wolfson L, Del Valle L, Ochaion A, Cohen S, Patoka R, Zozulya G, Barer F, Atar E, Piña-Oviedo S, Perez-Liz G, Castel D, Fishman P
Can-Fite BioPharma, Petah Tikva, Israel.
Arthritis Rheum. 2009 Oct;60(10):3061-71. doi: 10.1002/art.24817.
Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A(3) adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model.
OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 microg/kg given twice daily) was initiated. The A(3) adenosine receptor antagonist MRS1220 (100 microg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses.
CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-kappaB signaling pathway, resulting in down-regulation of tumor necrosis factor alpha. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes.
CF101 deregulated the NF-kappaB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.
研究表明类风湿性关节炎（RA）和骨关节炎（OA）具有共同特征。高选择性A(3)腺苷受体激动剂CF101最近被定义为一种治疗RA的强效抗炎药。本研究的目的是在实验动物模型中研究CF101对OA临床和病理表现的影响。
用碘乙酸钠诱导大鼠发生OA，疾病发作后开始口服CF101（100微克/千克，每日两次）。在CF101治疗前30分钟口服给予A(3)腺苷受体拮抗剂MRS1220（100微克/千克，每日两次）。通过测量膝关节直径和进行影像学分析来监测OA临床评分。用苏木精和伊红、番红O-固绿或甲苯胺蓝染色后进行组织学分析，并根据改良的曼金系统对组织学变化进行评分。通过蛋白质印迹法检测信号蛋白；通过免疫组织化学和TUNEL分析检测细胞凋亡。
CF101使膝关节直径显著减小，并改善了X线片上的变化。给予MRS1220可抵消CF101的作用。CF101可预防软骨损伤、破骨细胞/骨赘形成和骨质破坏。此外，CF101显著减少了血管翳形成和淋巴细胞浸润。从机制上讲，CF101诱导NF-κB信号通路失调，导致肿瘤坏死因子α下调。因此，CF101诱导浸润膝关节的炎性细胞凋亡；然而，它可防止软骨细胞凋亡。
CF101使OA发病机制中涉及的NF-κB信号通路失调。CF101诱导炎性细胞凋亡并起到软骨保护剂的作用，这表明它可能是治疗OA的合适候选药物。
