中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (5): 968-977.doi: 10.12307/2025.293

• 骨组织构建 bone tissue construction • 上一篇    下一篇

成纤维细胞生长因子受体1抑制剂对胶原诱导关节炎模型大鼠骨破坏的影响

韩海慧1，2，3，孟晓辉1，2，3，徐  博1，2，3，冉  磊1，2，3，施  杞1，2，3，肖涟波1，2，3   

  1. 1上海中医药大学，上海市  201203；2上海中医药大学附属光华医院，上海市  200052；3上海市中医药研究院中西医结合关节炎研究所，上海市200052
  • 收稿日期:2024-01-15 接受日期:2024-02-29 出版日期:2025-02-18 发布日期:2024-06-03
  • 通讯作者: 肖涟波，博士，主任医师，博士生导师，上海中医药大学，上海市 201203；上海中医药大学附属光华医院，上海市 200052；上海市中医药研究院中西医结合关节炎研究所，上海市 200052
  • 作者简介:韩海慧，男，1992年生，江苏省如东县人，汉族，上海中医药大学在读博士，医师，主要从事骨关节疾病免疫治疗相关研究。
  • 基金资助:
    上海市自然科学基金面上项目(22ZR1453100)，项目负责人：肖涟波；长宁区卫健委重点专科(20231003)，项目负责人：肖涟波

Effect of fibroblast growth factor receptor 1 inhibitor on bone destruction in rats with collagen-induced arthritis 

Han Haihui1, 2, 3, Meng Xiaohui1, 2, 3, Xu Bo1, 2, 3, Ran Lei1, 2, 3, Shi Qi1, 2, 3, Xiao Lianbo1, 2, 3   

  1. 1Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; 2Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China; 3Institute of Arthritis Research of Integrated Traditional Chinese and Western Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200052, China
  • Received:2024-01-15 Accepted:2024-02-29 Online:2025-02-18 Published:2024-06-03
  • Contact: Xiao Lianbo, MD, Chief physician, Doctoral supervisor, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China; Institute of Arthritis Research of Integrated Traditional Chinese and Western Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200052, China
  • About author:Han Haihui, MD candidate, Physician, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200052, China; Institute of Arthritis Research of Integrated Traditional Chinese and Western Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200052, China
  • Supported by:
    Shanghai Natural Science Foundation (General Program), No. 22ZR1453100 (to XLB); Changning District Health Commission Key Specialties, No. 20231003 (to XLB)

PDF

136

摘要：




文题释义：
类风湿性关节炎：是一种慢性、系统性的自身免疫性疾病，主要影响关节，特别是手和足部的小关节。这种疾病的特点是关节的持续性炎症，最终导致关节结构的破坏和功能障碍。骨破坏是类风湿关节炎最严重的并发症之一，它不仅影响患者的生活质量，还可能导致永久性残疾。
成纤维细胞生长因子受体1(fibroblast growth factor receptor 1，FGFR1)：是一种酪氨酸激酶受体，通过与其配体成纤维细胞生长因子结合而被激活，导致受体二聚化(配对)、自磷酸化和下游信号通路的激活，影响细胞的正常功能和疾病状态，其异常表达或功能失调与多种疾病的发生有关，是当前生物医学研究的一个重要焦点。

背景：课题组前期的研究表明靶向成纤维细胞生长因子受体1(fibroblast growth factor receptor 1，FGFR1)可能是治疗类风湿性关节炎的有效靶点。
目的：探讨FGFR1抑制剂(PD173074)对胶原诱导关节炎模型大鼠骨破坏的影响。
方法：将25只雌性SD大鼠随机分为5组，正常对照组、模型组、甲氨蝶呤组、PD173074低剂量组、PD173074高剂量组。除正常对照组外，其余各组大鼠建立Ⅱ型胶原诱导关节炎模型。造模成功后正常组及模型组大鼠腹腔注射无菌PBS，甲氨蝶呤组药物注射剂量为1.04 mg/kg，PD173074低剂量组和高剂量组药物注射剂量分别为5，20 mg/kg，1次/周。给药4周后取材，观察大鼠临床症状以及关节肿胀情况，踝关节Micro-CT三维重建及分析，观察踝关节病理变化，检测关节周围血管生成情况及核因子κB受体活化因子配体的表达，检测关节滑膜中p-FGFR1、血管内皮生长因子A、抗酒石酸酸性磷酸酶的表达，观察肝、脾、肾病理变化并计算肝、脾、肾指数。
结果与结论：①PD173074能够减轻模型大鼠踝关节临床症状及关节肿胀，延缓骨质丢失，改善骨结构，减轻关节滑膜侵袭以及软骨骨侵蚀，降低关节周围破骨细胞数量，抑制关节滑膜组织中的血管生成，降低核因子κB受体活化因子配体的表达，抑制FGFR1磷酸化蛋白、抗酒石酸酸性磷酸酶和血管内皮生长因子A的蛋白表达。②大鼠肝、脾、肾病理观察表明经过PD173074治疗后无明显的毒副作用。③研究证明了FGFR1抑制剂能够延缓Ⅱ型胶原诱导关节炎模型大鼠关节炎症及骨破坏的进展，并抑制血管的生成。初步验证了PD173074在Ⅱ型胶原诱导关节炎模型中的治疗作用，其可能是通过抑制FGFR1磷酸化发挥作用，为寻找类风湿性关节炎新的治疗靶点提供了方向。                              
https://orcid.org/0000-0002-9074-7380(韩海慧)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 类风湿关节炎, PD173074, 成纤维细胞生长因子受体1, 胶原诱导型关节炎, 动物模型, 骨破坏, 血管生成

Abstract: BACKGROUND: Preliminary research by our group suggests that targeting fibroblast growth factor receptor 1 (FGFR1) may be an effective strategy for treating RA.
OBJECTIVE: To investigate the effects of an FGFR1 inhibitor (PD173074) on bone destruction in rats with collagen-induced arthritis. 
METHODS: Twenty-five female Sprague-Dawley rats were randomly divided into five groups: normal control group, model group, methotrexate group, low-dose PD173074 group, and high-dose PD173074 group. Except for the normal control group, rat models of type II collagen-induced arthritis were made in each group. After successful modeling, rats were injected intraperitoneally with sterile PBS in the normal and model groups, 1.04 mg/kg methotrexate in the methotrexate group, and 5 and 20 mg/kg in the low-dose group and high-dose PD173074 groups, once a week. After 4 weeks of drug administration, clinical symptoms and joint swelling in rats were observed. Micro-CT was used for three-dimensional reconstruction and analysis of the ankle joints. Pathological changes in the ankle joints were observed. Periarticular angiogenesis and the expression of receptor activator of nuclear factor-κB ligand were detected. The expression levels of p-FGFR1, vascular endothelial growth factor A, and tartrate-resistant acid phosphatase in the synovial membrane were measured. Pathological changes in the liver, spleen, and kidney were observed and liver, spleen, and kidney indices were calculated. 
RESULTS AND CONCLUSION: PD173074 could alleviate clinical symptoms and joint swelling, delay bone loss, improve bone structure, reduce synovial invasion and cartilage bone erosion, reduce the number of periarticular osteoclasts, inhibit angiogenesis in synovial tissues, reduce the expression of receptor activator of nuclear factor-κB ligand, and inhibit the expression of FGFR1 phosphorylated protein, tartrate-resistant acid phosphatase and vascular endothelial growth factor A. Pathologic observation of the liver, spleen and kidney in rats showed no obvious toxic side effects after PD173074 treatment. To conclude, the FGFR1 inhibitor can delay the progression of joint inflammation and bone destruction and inhibit angiogenesis in the rat model of type II collagen-induced arthritis. The therapeutic effect of PD173074 has been preliminarily validated in the type II collagen-induced arthritis model and may act by inhibiting FGFR1 phosphorylation, which provides a direction for the search of new therapeutic targets for rheumatoid arthritis.   

Key words: rheumatoid arthritis, PD173074, fibroblast growth factor receptor 1, collagen-induced arthritis, animal model, bone destruction, angiogenesis

中图分类号: