Gravallese E M
Department of Medicine, Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, 4 Blackfan Circle, Room 241, Boston, MA 02115, USA.
Ann Rheum Dis. 2002 Nov;61 Suppl 2(Suppl 2):ii84-6. doi: 10.1136/ard.61.suppl_2.ii84.
Rheumatoid arthritis (RA) is characterised by the presence of an inflammatory synovitis accompanied by destruction of joint cartilage and bone. Destruction of cartilage matrix results predominantly from the action of connective tissue proteinases released by RA synovial tissues, chondrocytes, and pannus tissue. Several lines of evidence in RA and in animal models of arthritis support a role for osteoclasts in the pathogenesis of bone erosions. RA synovial tissues produce a variety of cytokines and growth factors that may increase osteoclast formation, activity, and/or survival. These include interleukin 1alpha (IL1alpha) and beta, tumour necrosis factor alpha (TNFalpha), IL11, IL17, and macrophage colony stimulating factor (M-CSF). Receptor activator of NFkappaB ligand (RANKL) is an essential factor for osteoclast differentiation and also functions to augment T cell-dendritic cell cooperative interactions. CD4+ T cells and synovial fibroblasts derived from RA synovium are sources of RANKL. Furthermore, in collagen induced arthritis (CIA), blockade with osteoprotegerin (OPG), a decoy receptor for RANKL, results in protection from bone destruction. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, arthritis was generated in the RANKL knockout mouse using a serum transfer model. Despite ongoing inflammation, the degree of bone erosion in arthritic RANKL knockout mice, as assessed by microcomputed tomography and correlated histopathological analysis, was dramatically reduced compared with that seen in arthritic control mice. Cartilage damage was present in both the arthritic RANKL knockout mice and in arthritic control littermates, with a trend toward milder cartilage damage in the RANKL knockout mice. This study supports the hypothesis that osteoclasts play an important part in the pathogenesis of focal bone erosion in arthritis, and reveals distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis. Future directions for research in this area include the further investigation of a possible direct role for the RANKL/RANK/OPG system in cartilage metabolism, and the possible role of other cell types and cytokines in bone erosion in arthritis.
类风湿关节炎（RA）的特征是存在炎症性滑膜炎，并伴有关节软骨和骨破坏。软骨基质的破坏主要源于RA滑膜组织、软骨细胞和血管翳组织释放的结缔组织蛋白酶的作用。RA及关节炎动物模型中的多条证据支持破骨细胞在骨侵蚀发病机制中的作用。RA滑膜组织产生多种细胞因子和生长因子，可能会增加破骨细胞的形成、活性和/或存活。这些因子包括白细胞介素1α（IL1α）和β、肿瘤坏死因子α（TNFα）、IL11、IL-17和巨噬细胞集落刺激因子（M-CSF）。核因子κB受体活化因子配体（RANKL）是破骨细胞分化的关键因子，也具有增强T细胞-树突状细胞协同相互作用的功能。来自RA滑膜的CD4+ T细胞和滑膜成纤维细胞是RANKL的来源。此外，在胶原诱导的关节炎（CIA）中，用骨保护素（OPG）（一种RANKL的诱饵受体）进行阻断可防止骨破坏。为了进一步评估破骨细胞在关节炎局部骨侵蚀中的作用，使用血清转移模型在RANKL基因敲除小鼠中诱发关节炎。尽管炎症持续存在，但通过微计算机断层扫描评估并结合组织病理学分析发现，与关节炎对照小鼠相比，关节炎RANKL基因敲除小鼠的骨侵蚀程度显著降低。关节炎RANKL基因敲除小鼠和关节炎对照同窝小鼠均存在软骨损伤，RANKL基因敲除小鼠的软骨损伤有减轻趋势。本研究支持破骨细胞在关节炎局部骨侵蚀发病机制中起重要作用这一假说，并揭示了该关节炎动物模型中软骨破坏和骨侵蚀的不同机制。该领域未来的研究方向包括进一步研究RANKL/RANK/OPG系统在软骨代谢中可能的直接作用，以及其他细胞类型和细胞因子在关节炎骨侵蚀中的可能作用。
