Pathological role of osteoclast costimulation in arthritis-induced bone loss
Pathological role of osteoclast costimulation in arthritis-induced bone loss
复制标题
DOI：
10.1073/pnas.0701971104
复制
发表时间：
2007-07-03
影响因子：
11.1
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Ochi, Sae;Shinohara, Masahiro;Takayanagi, Hiroshi
异常的T细胞免疫应答诱导炎性细胞因子如TNF-α的异常表达，导致破骨细胞介导的自体免疫性关节炎中的骨侵蚀和骨质疏松症。然而，关节炎中破骨细胞生成增强的机制还不完全清楚。我们发现TNF-α通过诱导成对的Ig样受体-A（PIR-A）（一种NF-κ B受体激活剂（RANK）的共刺激受体）增强破骨细胞前体细胞的破骨细胞生成潜能而促进炎性骨丢失。事实上，在Fc受体共同γ亚基或β（2）-微球蛋白缺陷的小鼠中，由异常TNF-α表达引起的骨侵蚀和骨质疏松症而非炎症得到改善，其中PIR-A和PIR-A受体的表达分别受损。这些结果确立了RANK共刺激受体在关节炎骨丢失中的病理作用，并可能为炎症性疾病的未来治疗提供分子基础。
Abnormal T cell immune responses induce aberrant expression of inflammatory cytokines such as TNF-alpha, leading to osteoclastmediated bone erosion and osteoporosis in autclimmune arthritis. However, the mechanism underlying enhanced osteoclastogenesis in arthritis is not completely understood. Here we show that TNF-a contributes to inflammatory bone loss by enhancing the osteoclastogenic potential of osteoclast precursor cells through inducing paired Ig-hke receptor-A (PIR-A), a costimulatory receptor for receptor activator of NF-kappa B (RANK). In fact, bone erosion and osteoporosis, but not inflammation, caused by aberrant TNF-a expression were ameliorated in mice deficient in Fc receptor common gamma subunit or beta(2)-microglobulin, in which the expression of PIR-As and PIR-A figands is impaired, respectively. These results establish the pathological role of costimulatory receptors for RANK in bone loss in arthritis and may provide a molecular basis for the future therapy of inflammatory diseases.