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

骨性关节炎是老年人群中的常见病，由关节软骨损伤引起。到目前为止，老化或机械应力一直被认为是关节改变的原因，然而最近的研究表明，炎症介质在关节退化中起着重要作用。作为我们先前研究(项目编号11671461)的结果，我们发现骨桥蛋白、YKL-39和中间层蛋白的自身抗体存在于骨桥蛋白、YKL-39和中间层蛋白(CILP)的血清中。本课题对骨性关节炎的免疫机制进行了深入的研究，取得了以下成果。炎症反应的存在：恭维受体C5aR在OA软骨细胞中有表达。关节软骨细胞分泌趋化因子MCP-1、MIP-1和RANTES，其受体CCR2和CCR5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，促进基质金属蛋白酶的产生，抑制软骨细胞蛋白多糖的合成。YKL-39和CILP的致关节炎作用：YKL-39和CILP免疫可诱导某些品系的小鼠慢性和少发关节炎。此外，对相关表位进行了研究。组织学上，接种CILP后滑膜炎和关节受累，并发现异位骨化。血管圈样组织的存在：骨关节炎软骨表面多见血管圈样软组织，该组织具有分解代谢特征，表达IL-1和基质金属蛋白酶-3.1。软骨细胞与T细胞的相互作用：软骨细胞与自体T细胞的直接接触增加了基质金属蛋白酶和RANTES的产生，导致进一步的关节退化。未来计划：目前正在研究从OA模型动物到正常受试者的免疫细胞转移。

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.