类风湿性关节炎(RA)是免疫介导的,影响滑膜关节的炎症性疾病,以滑膜组织的炎症变化为特征,软骨,骨头,在关节外结构中较不常见。多西他赛(DTX)是一种半合成抗肿瘤药物。肽基精氨酸脱亚胺酶4型(PAD4)在RA滑膜中的巨噬细胞和嗜中性粒细胞中表达。它们的有效性在于产生抗环状瓜氨酸化肽抗体(ACPA)靶向的瓜氨酸化新表位。
目的:评估DTX在RA中的抗炎作用以及甲氨蝶呤对PAD4的影响,以研究其作为RA生物标志物的潜力。
方法:雄性Wistar大鼠40只,分为5组,每组8只。健康大鼠形成对照组。第二组至第五组用完全弗氏佐剂诱导。第三组隔天接受剂量为1mg/kg的DTX,由初步实验确定。第四组腹腔内给予甲氨蝶呤1mg/kg/周。第五组同时用一半剂量的DTX和甲氨蝶呤治疗。
结果:DTX组的关节炎指数和膝关节周围明显下降。体重无显著差异,血小板-淋巴细胞比率,两组之间的白细胞计数。嗜中性淋巴细胞比率与ACPA呈弱相关性,而PAD4与RA标志物表现出良好的相关性。ACPA级别,PAD4,TNF-α,IL-1β,与诱导组相比,DTX组的VEGF和VEGF明显下降(p<0.05)。
结论:DTX降低了完全弗氏佐剂诱导的大鼠的进展和关节破坏,这可能是由于抑制了PAD4,TNF-α,IL-1β,VEGF,和ACPA。此外,甲氨蝶呤表现出抗PAD4作用。
Rheumatoid arthritis (RA) is immune-mediated, inflammatory disease that affects synovial joints, and characterized by inflammatory changes in synovial tissue, cartilage, bone, and less commonly in extra-articular structures. Docetaxel (DTX) is a semi-synthetic anti-neoplastic medication. Peptidyl-arginine deiminase type 4 (
PAD4) is expressed in macrophages and neutrophils in RA synovial membrane. Their effectiveness is in producing anti-cyclic citrullinated peptide antibodies (ACPA)-targeted citrullinated neoepitopes.
OBJECTIVE: To evaluate the anti-inflammatory effects of DTX in RA and the effect of methotrexate on
PAD4 to investigate its potential as an RA biomarker.
METHODS: Forty male Wistar rats were divided into five groups of eight rats. Healthy rats formed the control group. The Second Group to Fifth group were induced with Complete Freund\'s adjuvant. The third group received DTX at a dosage of 1 mg/kg on alternate days, as determined by a preliminary experiment. The fourth group was given 1 mg/kg/week of methotrexate intraperitoneally. The fifth group was treated with a half dose of DTX and methotrexate simultaneously.
RESULTS: Significant Arthritis index and knee joint circumference decrease in the DTX group. No significant difference in body weight, platelet-lymphocyte ratio, and white blood cell count between the groups. Neutrophile lymphocyte ratio showed weak correlation with ACPA, while
PAD4 showed good correlation with RA markers. Level of ACPA, PAD4, TNF-α, IL-1β, and VEGF significantly decreased in the DTX group than induction group (p < 0.05).
CONCLUSIONS: DTX reduces the progression and joint destruction in rats induced by Complete Freund\'s Adjuvant which may due to inhibition of
PAD4, TNF-α, IL-1β, VEGF, and ACPA. Also, methotrexate exhibited anti
PAD4 effect.