Therapeutic research for osteoporosis with rheumatoid arthritis

骨质疏松症合并类风湿性关节炎的治疗研究

• 批准号: 15591074
• 负责人: OKADA Yosuke
• 金额: $ 2.24万
• 依托单位: University of Occupational and Environmental Health, Japan
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591074/
• 关键词: M-CSF; rheumatoid arthritis; osteoblasts; osteoclasts; bone resorption; endothelial cells; RANKL; Gene chip; FGF-2; ヘパラン硫酸プロテオグリカン; ICAM-1; β_1インテグリン; 骨粗鬆症

Objective. Periarticular osteoporosis and joint destruction are major complications in rheumatoid arthritis (RA), caused by osteoclast-mediated bone resorption. However, the mechanisms of monocyte osteoclast maturation and role of rheumatoid arthritis endothelial cells (RAEC) in the control of osteoclastogenesis remain unclear. The present study was designed to determine the most important factors that influence monocyte accumulation and osteoclast formation among the many factors produced by RAEC.Methods. We analyzed the expression profiles of various genes in human endothelial cells from various organs (RA synovium, umbilical vein, skin, liver sinusoid, renal glomerulus and brain) using oligonucleotide microarrays. The microarray data were assessed by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and immunostaining of RA synovia. Migration of monocytes was assessed by the chemotactic chamber EZ-TAXIScanTM. Tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell formation was observed by microscopy.Results. Among many epithelial-expressed factors, macrophage-colony stimulating factor (M-CSF) gene was abundantly expressed specifically in RAEC. Fibroblast growth factor-2 (FGF-2) gene was also overexpressed on RAEC. Migration of monocytes and osteoclast formation in co-cultures promoted by culture supernatants of RAEC were inhibited by M-CSF neutralizing antibody.Conclusion. M-CSF produced by RAEC is involved in osteoclastogenesis from monocytes ; migration, and TRAP-positive multi-nuclear cell formation, resulting in joint destruction of RA.

Objective.类风湿关节炎（RA）的主要并发症是关节周围骨质疏松和关节破坏，由破骨细胞介导的骨吸收引起。然而，单核细胞破骨细胞成熟的机制和类风湿关节炎内皮细胞（RAEC）在控制破骨细胞生成中的作用仍不清楚。本研究旨在确定RAEC产生的众多因素中影响单核细胞积聚和破骨细胞形成的最重要因素。方法。我们使用寡核苷酸微阵列分析了来自各种器官（RA滑膜、脐静脉、皮肤、肝窦、肾小球和脑）的人内皮细胞中各种基因的表达谱。微阵列数据通过实时定量聚合酶链反应、酶联免疫吸附试验和RA滑膜免疫染色进行评估。通过趋化室EZ-TAXIScanTM评估单核细胞的迁移。抗酒石酸酸性磷酸酶（TRAP）阳性多核细胞的形成通过显微镜观察。巨噬细胞集落刺激因子（macrophage-colony stimulating factor，M-CSF）基因在RAEC中特异性表达。成纤维细胞生长因子-2（FGF-2）基因在RAEC上也有过表达。M-CSF中和抗体可抑制RAEC培养上清促进的单核细胞迁移和破骨细胞形成。由RAEC产生的M-CSF参与单核细胞的破骨细胞生成、迁移和TRAP阳性多核细胞形成，导致RA的关节破坏。

项目成果

岡田洋右, 田中良哉: "抗炎症治療の滑膜病変に対する効果"腎と骨代謝. 16. 51-57 (2003)

Hiroaki Okada、Yoshiya Tanaka：“抗炎治疗对滑膜病变的影响”《肾脏和骨代谢》16. 51-57 (2003)。

Y.Okada, A.Montero, X.Zhang, et al.: "Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone."J Biol Chem. 278. 21258-21266 (2003)

Y.Okada、A.Montero、X.Zhang 等人：“Fgf2 缺失小鼠骨髓培养物中破骨细胞形成对甲状旁腺激素的反应受损。”J Biol Chem。

Fibroblast growth factor-2 induces receptor activator of nuclear factor kappa B ligand expression and osteoclast maturation by binding to heparin sulfate proteoglycan on rheumatoid synovial fibroblasts.

成纤维细胞生长因子 2 通过与类风湿滑膜成纤维细胞上的硫酸肝素蛋白聚糖结合，诱导核因子 kappa B 受体激活剂配体表达和破骨细胞成熟。

• 发表时间: 2004
• 期刊: Arthritis Rheum 50
• 作者: Nakano K;et al.
• 通讯作者: et al.

Y.Okada, C.Pilbeam, L.Raisz, Y.Tanaka: "Role of cyclooxygenase-2 in bone resorption."J UOEH. 25. 185-195 (2003)

Y.Okada、C.Pilbeam、L.Raisz、Y.Tanaka：“环氧合酶 2 在骨吸收中的作用。”J UOEH。

Y.Tanaka, Y.Okada, T.Nakamura: "Inter- and infra-cellular signaling in secondary osteoporosis."J Bone Miner Metab. 21. 61-66 (2003)

Y.Tanaka、Y.Okada、T.Nakamura：“继发性骨质疏松症中的细胞间和细胞内信号传导。”J Bone Miner Metab。