Investigating the Role of Fc Receptors in the Pathogenesis of Osteoarthritis

描述(由申请人提供)： 目前治疗骨性关节炎的方法只是缓解晚期疾病的症状，而不是抑制导致疾病的过程。更好地了解骨性关节炎的发病机制无疑将产生新的治疗方法。尽管骨性关节炎长期以来被认为是一种纯粹的机械性疾病，但越来越明显的是，它也涉及炎症和免疫细胞的激活。骨性关节炎患者的滑膜组织含有炎性细胞因子，并渗透有天然免疫细胞和获得性免疫细胞，滑膜炎症的存在预示着软骨的更快速破坏。这些渗入的免疫细胞表达Fc受体(FCR)，通常通过与抗体结合来预防感染，从而触发炎症和细胞毒性介质的释放。然而，FCR介导的信号的异常激活或调节可导致炎症性和自身免疫性疾病。我们已经获得证据表明，FCR在骨性关节炎的发病机制中也起着核心作用。我们发现，在一种骨性关节炎的小鼠模型中，缺乏共同的？-链的小鼠对软骨退化具有抵抗力。缺乏Fc？RIII的小鼠也有抵抗力，Fc？RIII不是通过链传递信号，但已被证明可以介导自身抗体诱导的组织损伤和炎症。我们假设，一个或多个激活的FCR通过诱导表达FCR的免疫细胞释放炎症、血管活性、细胞毒性和降解分子，进而促进OA的滑膜炎、细胞死亡和软骨侵蚀，从而参与OA的发病。抗原结合抗体激活FCR，针对关节成分的抗体存在于OA滑液、滑膜组织和软骨中。在小鼠身上的发现表明，针对各种关节成分的抗体可以引起炎性关节破坏。这种抗体可能是在软骨成分暴露于免疫系统后产生的--由于软骨机械性破坏--并通过激活FCR而促进OA的炎性关节破坏。我们建议使用基因缺陷小鼠、已建立的骨关节炎小鼠模型和来自骨关节炎患者的样本来(I)确定激活FCR是否促进小鼠骨关节炎，以及它们是否通过激活肥大细胞、巨噬细胞或其他免疫细胞来促进；(Ii)确定表达FCR的免疫细胞在人骨关节炎发育早期多早渗入滑膜关节；(Iii)确定FCR表达水平或免疫细胞激活水平是否与骨关节炎相关的炎症水平或疾病严重程度相关；以及(Iv)确定人骨关节炎软骨碎片是否能够以依赖于FCR的方式激活固有免疫细胞。目前正在开发几种靶向FCR的方法来治疗炎症性疾病。靶向FCR可以防止触发一系列不同的炎性介质，可能被证明比靶向单一的炎性介质更有效(后者是一种迄今在OA中被证明不成功的方法)。因此，通过阐明FCRs在骨性关节炎中的作用，拟议研究的成功可能会为骨性关节炎的治疗开辟新的途径，对此迫切需要疾病修正治疗。

DESCRIPTION (provided by applicant): Current therapies for OA simply alleviate symptoms of advanced disease rather than inhibit the processes that drive the disease. A better understanding of the mechanisms underlying the pathogenesis of OA would undoubtedly yield new therapeutic approaches. Although OA was long considered a purely mechanical disorder, it is becoming clear that it also involves inflammation and activation of immune cells. Synovial tissues of individuals with OA contain inflammatory cytokines and are infiltrated with both innate and adaptive immune cells, and the presence of synovial inflammation predicts more rapid cartilage destruction. These infiltrating immune cells express Fc receptors (FcRs), which normally serve to protect against infection by binding to antibodies and thereby triggering the release of inflammatory and cytotoxic mediators. However, aberrant activation or regulation of FcR-mediated signaling can lead to inflammatory and autoimmune diseases. We have garnered evidence that FcRs also play a central role in the pathogenesis of OA. We found that mice lacking the common ?-chain, through which several of the activating FcRs signal, are resistant to cartilage degeneration in a mouse model of OA. Mice deficient specifically in Fc?RIII, which does not signal through the ¿-chain but has been shown to mediate autoantibody-induced tissue damage and inflammation, were also resistant. We hypothesize that one or more activating FcR contributes to the pathogenesis of OA by inducing FcR-expressing immune cells in OA synovial tissue to release inflammatory, vasoactive, cytotoxic, and degradative molecules that in turn contribute to the synovitis, cell death, and cartilage erosion characteristic of OA. Antigen-bound antibodies activate FcRs, and antibodies directed against joint components are present in OA synovial fluid, synovial tissue, and cartilage. Findings in mice indicate that antibodies to various joint components can elicit inflammatory joint destruction. It is possible that such antibodies develop following exposure of cartilage components to the immune system- owing to mechanical cartilage breakdown-and contribute to inflammatory joint destruction in OA by activating FcRs. We propose to use genetically deficient mice, an established mouse model of OA, and samples from patients with OA to (i) determine whether activating FcRs promote mouse OA, and whether they do so by activating mast cells, macrophages, or other immune cells; (ii) determine how early in the development of human OA FcR-expressing immune cells infiltrate the synovial joints; (iii) determine whether levels of FcR expression or levels of immune-cell activation correlate with levels of OA-associated inflammation or with disease severity in human OA; and (iv) determine whether debris from human OA cartilage can activate innate immune cells in an FcR-dependent manner. Several approaches to targeting FcRs are being developed for the treatment of inflammatory disorders. Targeting FcRs, which could prevent the triggering of a cascade of different inflammatory mediators, may prove more therapeutically efficacious than targeting a single inflammatory mediator (the latter being an approach that has so far proven unsuccessful in OA). Thus, by shedding light on the role of FcRs in OA, success of the proposed studies could open up new avenues for the treatment of OA, for which disease- modifying treatments are urgently needed.