Influence of immune mechanism on aging in articular cartilage, -Immune response and responsible proteins in osteoarthritis-

免疫机制对关节软骨老化的影响，-骨关节炎中的免疫反应和相关蛋白-

• 批准号: 13671547
• 负责人: NAKAMURA Hiroshi
• 金额: $ 2.05万
• 依托单位: St. Marianna University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671547/
• 关键词: osteoarthritis; Immune response; inflammation; animal model; YKL-39; cartilage intermediate layer protein (CLIP); pannus; CILP; 関節炎

Osteoarthritis (OA) is frequent during aged population and is caused by damage of articular cartilage. As far, :aging or mechanical stress have been considered to be a cause of articular change, however recent studies show that inflammatory mediators have an important role in the articular degradation. As a result of our previous study (project No. 11671461), we showed that T cells infiltrated into synovial tissue from patients with OA and autoantibodies against osteopontin, YKL-39 and intermediate layer protein (CILP) were present in sera of the patients. In this term, the immune mechanism in osteoarthritis (OA) was investigated further and following results were obtained.1. The presence of inflammatory reactions : C5aR, one of compliment receptors was expressed in OA chondrocytes. Chemokines such as MCP-1, MIP-1 and RANTES are secreted from articular chondrocytes and their receptors (CCR2 and CCR5) were expressed in chondrocytes. Among these, RANTES and MCP-1 had catabolic effects on articular cartilage enhancing MMP production and suppressing proteoglycan synthesis from chondrocytes.1. Arthritogenicity of YKL-39 and CILP : Immunization of YKL-39 and CILP induced chronic and oligo-arthritis in some mouse strains. Moreover, responsible epitopes were investigated. Histrologically, synovitis and articular involvement were shown and ectopic ossification was found following CILP immunization.1. The presence of pannus-like tissue : Pannus-like soft tissue was frequently found on the surface of OA cartilage and the tissue had catabolic characteristics expressing IL-1 and MMP-3.1. Interaction of chondrocytes with T cells : Direct contact of chondrocytes with autologous T cells enhanced MMP and RANTES production leading further articular degradation.1. Future plan : Transfer of immune cells from OA model animals to normal subjects are investigated at present.

骨关节炎（Osteoarthritis，OA）是一种常见的老年性疾病，主要是由于关节软骨的损伤所致.到目前为止，老化或机械应力被认为是关节变化的原因，然而最近的研究表明，炎症介质在关节退化中起重要作用。作为我们先前研究（项目编号11671461）的结果，我们发现T细胞浸润到OA患者的滑膜组织中，患者血清中存在抗骨桥蛋白、YKL-39和中间层蛋白（CILP）的自身抗体。本课题对骨关节炎（OA）的免疫机制进行了深入的研究，取得了以下结果.炎症反应的存在：补体受体C5 aR在OA软骨细胞中表达。趋化因子如MCP-1、MIP-1和RANTES由关节软骨细胞分泌，其受体（CCR 2和CCR 5）在软骨细胞中表达。其中，RANTES和MCP-1对关节软骨具有分解代谢作用，促进软骨细胞MMP的产生，抑制软骨细胞蛋白多糖的合成. YKL-39和CILP的致关节炎性：YKL-39和CILP的免疫在一些小鼠品系中诱导慢性和少关节炎。此外，负责表位进行了调查。组织学上，CILP免疫后出现滑膜炎和关节受累，并发现异位骨化.血管翳样组织的存在：在OA软骨表面经常发现血管翳样软组织，该组织具有表达IL-1和MMP-3.1的分解代谢特征。软骨细胞与T细胞的相互作用：软骨细胞与自体T细胞的直接接触增强了MMP和RANTES的产生，导致进一步的关节降解.未来计划：目前正在研究将免疫细胞从OA模型动物转移到正常受试者。

项目成果

Tsuruha J et al.: "Implication of cartilage intermediate layer protein in cartilage destruction in subsets of patients with osteoarthritis and rheumatoid arthritis"Arthritis Rheum.. 44. 838-845 (2001)

Tsuruha J 等人：“软骨中间层蛋白对骨关节炎和类风湿关节炎患者亚组软骨破坏的影响”Arthritis Rheum.. 44. 838-845 (2001)

Nakamura H, Nishioka K: "Effects of glucosamine/chondroitin supplement on osteoarthritis : involvement of PGE2 and YKL-40"Jpn Rheum Joint Surg. 21. 175-184 (2002)

Nakamura H、Nishioka K：“葡萄糖胺/软骨素补充剂对骨关节炎的影响：PGE2 和 YKL-40 的参与”Jpn Rheum Joint Surg。

Tsuruha J et al.: "Implication of cartilage intermediate layer protein in subsets of patients with osteoarthritis and rheumatoid arthritis"Arthritis & Rheumatism. Apr;44(4). 838-845 (2001)

Tsuruha J 等人：“软骨中间层蛋白对骨关节炎和类风湿性关节炎患者亚群的影响”关节炎

Shibakawa A et al.: "Links Presence of pannus-like tissue on osteoarthritic cartilage and its histological character"Osteoarthritis Cartilage. 11. 133-140 (2003)

Shibakawa A 等人：“骨关节炎软骨上血管翳样组织的存在及其组织学特征”骨关节炎软骨。

Sakata M, Tsuruha J, Masuko-Hongo K, Nakamura H, Matsui T, Sudo A, et al: "Autoantibodies to osteopontin in patients with osteoarthritis and rheumatoid arthritis"J Rheumatol. 28. 1492-1495 (2001)

Sakata M、Tsuruha J、Masuko-Hongo K、Nakamura H、Matsui T、Sudo A 等人：“骨关节炎和类风湿性关节炎患者中骨桥蛋白的自身抗体”J Rheumatol。