Pettit A R, Walsh N C, Manning C, Goldring S R, Gravallese E M
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
Rheumatology (Oxford). 2006 Sep;45(9):1068-76. doi: 10.1093/rheumatology/kel045. Epub 2006 Feb 20.
Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappaB (RANK) in RA at sites of articular bone erosion.
Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannus-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion.
Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression.
The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.
核因子κB受体活化因子配体（RANKL）和骨保护素（OPG）已被证明是破骨细胞生成和活性的关键调节因子。此外，RANKL被认为是类风湿关节炎（RA）中骨侵蚀的重要介质。然而，尚未研究RANKL和OPG在血管翳侵入骨部位的表达情况。本研究旨在通过检查RA关节骨侵蚀部位RANKL、OPG和核因子κB受体活化因子（RANK）的蛋白表达模式，进一步阐明该细胞因子系统对RA中破骨细胞生成及随后骨侵蚀的作用。
收集17例RA患者20次手术的组织作为废弃材料。6个样本仅包含远离骨的滑膜或腱鞘滑膜，4个样本包含血管翳 - 骨界面及相邻滑膜，10个样本同时包含远离骨的滑膜和血管翳 - 骨界面及相邻滑膜。采用免疫组织化学方法，对紧邻和远离骨侵蚀部位的RANKL、RANK和OPG蛋白表达的细胞模式进行表征。
RANKL蛋白的细胞表达在骨微环境中相对受限；染色呈局灶性，主要局限于血管翳 - 骨界面破骨细胞介导的侵蚀部位以及软骨下骨侵蚀部位。这些部位也存在表达RANK的破骨细胞前体细胞。在远离骨的滑膜中的许多细胞中观察到OPG蛋白表达，但在骨侵蚀部位更有限，尤其是在与RANKL表达相关的区域。
RA骨侵蚀部位RANKL和OPG的表达模式以及表达RANK的破骨细胞前体细胞的存在，有助于形成有利于破骨细胞分化和活性的局部微环境。这些数据为RANKL参与关节炎诱导的关节破坏的发病机制提供了进一步证据。
