Mechanism of synovial cell proliferation and osteoclast differentiation in an in vitro model of bone destruction of cultured rheumatoid synovium

类风湿滑膜体外骨破坏模型中滑膜细胞增殖和破骨细胞分化的机制

• 批准号: 14570433
• 负责人: SUZUKI Yasuo
• 金额: $ 2.24万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570433/
• 关键词: RHEUMATOID ARTHRITIS; BONE DESTRUCTION; OSTEOCLAST; IN VITRO MODEL; RANKL; RANK; VEGF; SYNOVIOCYTE; TNFα

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis characterized by bone and cartilage destruction leading to loss of joint function. Characteristic histological features of RA are hyperplasia of synovial lining cells with a dense microvasculature and infiltration of inflammatory mononuclear cells with a formation of lymphoid follicles. Osteoclast is an only bone resorbing cells in the human bone tissues and recent studies demonstrated an involvement of osteoclasts or osteoclast-like cells in the pathogenesis of focal bone erosion in RA. Two factors, receptor activator of NF-KB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) are essential for the differentiation and activation of osteoclasts. However, the precise mechanism of osteoclast differentiation in the inflamed rheumatoid synovial tissues remains to be established. Recently, we have established a novel in vitro model of bone destruction by rheumatoid synovium^<20)>. This culture system employed osteocl … More ast-like cells differentiated from RA synovial tissue without any inducers. Using the in vitro culture model of bone destruction, we sought to determine what factors are involved in the development of osteoclast-like cells from RA synovium Formation of OC-like cells in the culture of RA synovial tissue was much higher than that in the culture OA synovial tissue and cultured rheumatoid synovium produced higher level of VEGF. VEGF receptor determined imniunohistochemically was expressed on the macrophages and OC like multinucleated cells. VEGF receptor 1-Fc chimeric protein inhibited OC-like cell and pit formation in a dose-dependent manner. Osteoprotegerin (OPG) and TNF receptor II-Fc chimeric protein also inhibited OC formation, but MCSF receptor-Fc chimeric protein was not effective. The RANK peptide that binds to RANKL inhibited OC-like cell formation in the cultured RA synovium.Our data suggest that both RANKL-dependent and independent signals might be involved in the formation of osteoclasts in the in vitro model of bone destruction. In addition, VEGF might be one of the key mediators of osteoclast-mediated bone destruction by RA synovium. Inhibition of RANKL/RANK and VEGF pathway could be a new strategy for the treatment of RA. Less

类风湿性关节炎（RA）是一种以骨和软骨破坏导致关节功能丧失为特征的慢性炎症性关节炎。RA的典型组织学特征是滑膜衬里细胞增生伴致密微血管和炎性单核细胞浸润伴淋巴滤泡形成。破骨细胞是人类骨组织中唯一的骨吸收细胞，近年来的研究表明破骨细胞或破骨细胞样细胞参与了RA局灶性骨侵蚀的发病机制。破骨细胞的分化和活化需要两种因子，即核因子κ B受体激活因子配体（RANKL）和巨噬细胞集落刺激因子（M-CSF）。然而，破骨细胞分化的炎症类风湿性滑膜组织的确切机制仍有待建立。最近，我们建立了一种新型的类风湿性滑膜骨破坏体外模型^<20）>。该培养体系采用骨细胞 ...更多信息 在无任何诱导剂的情况下，从RA滑膜组织中分化出ast样细胞。利用体外培养的骨破坏模型，我们试图确定哪些因素参与了RA滑膜破骨细胞样细胞的发育。RA滑膜组织培养中OC样细胞的形成远高于OA滑膜组织培养中的OC样细胞，并且培养的类风湿性关节炎滑膜产生更高水平的VEGF。免疫组化检测VEGF受体在巨噬细胞和OC样多核细胞上表达。VEGF受体1-Fc嵌合蛋白以剂量依赖性方式抑制OC样细胞和小窝形成。骨保护素（OPG）和TNF受体Ⅱ-Fc嵌合蛋白也能抑制OC的形成，而MCSF受体-Fc嵌合蛋白则无此作用。RANK肽与RANKL结合可抑制RA滑膜中OC样细胞的形成，提示RANKL依赖性和非依赖性信号均参与体外骨破坏模型中破骨细胞的形成。此外，VEGF可能是破骨细胞介导的RA滑膜骨破坏的关键介质之一。抑制RANKL/RANK和VEGF通路可能成为治疗RA的新策略。少

项目成果

鈴木康夫: "慢性関節リウマチにおける骨病変"日本臨床. 60巻. 407-417 (2002)

Yasuo Suzuki：“类风湿性关节炎的骨损伤”日本临床杂志 60. 407-417 (2002)。

Yasuo Suzuki: "Drug Therapy for Bone and Joint Disorders-Osteoporosis and Rheumatoid Arthritis-"Japan Pharmacists Education Center,(Tokyo). 3-27 (2002)

铃木康夫：“骨和关节疾病的药物治疗——骨质疏松症和类风湿性关节炎——”日本药剂师教育中心，（东京）。

Yasuo Suzuki: "Corticosteroid-induced osteoporosis-epidemiology, pathogenesis, and guideline for the prevention and treatment-"Osteoporosis Japan. vol 11, No.3. 427-436 (2003)

铃木康夫：“皮质类固醇引起的骨质疏松症-流行病学、发病机制和预防和治疗指南-”日本骨质疏松症。

Ichikawa Y, Kamatani N, Goto M, Kondo H, Saito T, Yasuo Suzuki, Torikal K, Hashimoto H, Miyasaka N, Yamanaka H, Yamamoto K, Fukao A, Mizushima Y.: "Phase II dose ranging study of leflunomide in Japan"J New Remedies & Clinics. Vol.52, No.7. 891-931 (2003)

Ichikawa Y、Kamatani N、Goto M、Kondo H、Saito T、Yasuo Suzuki、Torikal K、Hashimoto H、Miyasaka N、Yamanaka H、Yamamoto K、Fukao A、Mizushima Y.：“日本来氟米特的 II 期剂量范围研究

Yasuo Suzuki: "Guideline for the drug treatment of rheumatoid arthritis Leflunomide"Rinsho To Yakubutsuchiryou. Vol.22, No.12. 1102-1106 (2003)

铃木康夫：《类风湿性关节炎来氟米特药物治疗指南》Rinsho To Yakubutsuchiryou。