IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance
IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance
复制标题
DOI：
10.4049/jimmunol.170.5.2655
复制
发表时间：
2003-03-01
影响因子：
4.4
通讯作者：
van den Berg, WB
中科院分区：
文献类型：
--
作者：
Lubberts, E;van den Bersselaar, L;van den Berg, WB
IL-17是实验性关节炎中T细胞衍生的促炎细胞因子，是体外破骨细胞生成的刺激物。在本研究中，我们报道了IL-17过表达（AdIL-17）在11型胶原免疫小鼠膝关节对骨侵蚀和NF-kappaB配体滑膜受体激活物(RANKL)/ NF-kappaB受体激活物/骨保护素（OPG）表达的影响。局部IL-17促进破骨细胞骨破坏，在皮质骨、软骨下骨和小梁骨的骨侵蚀部位伴有明显的抗酒石酸酸性磷酸酶活性。特异性免疫组化发现，RANKL及其受体NF-kappaB受体激活剂在滑膜浸润和局灶性骨侵蚀部位加速表达。有趣的是，AdIL-17不仅增强了RANKL的表达，还强烈上调了滑膜中RANKL/OPG的比值。将AdIL-17胶原诱导关节炎组的关节炎小鼠与具有相似关节炎症临床评分的成熟胶原关节炎小鼠进行比较，发现后者组的RANKL/OPG比率和抗酒石酸盐酸性磷酸酶活性较低。有趣的是，在11型胶原免疫小鼠中，全身OPG治疗可预防局部AdIL-17基因转移引起的关节损伤。这些发现提示T细胞IL-17是RANKL表达的重要诱导剂，导致RANKL/OPG平衡丧失，刺激关节炎的破骨细胞生成和骨侵蚀。
IL-17 is a T cell-derived proinflammatory cytokine in experimental arthritis and is a stimulator of osteoclastogenesis in vitro. In this study, we report the effects of IL-17 overexpression (AdIL-17) in the knee joint of type 11 collagen-immunized mice on bone erosion and synovial receptor activator of NF-kappaB ligand (RANKL)/receptor activator of NF-kappaB/osteoprotegerin (OPG) expression. Local IL-17 promoted osteoclastic bone destruction, which was accompanied with marked tartrate-resistant acid phosphatase activity at sites of bone erosion in cortical, subchondral, and trabecular bone. Accelerated expression of RANKL and its receptor, receptor activator of NF-kappaB, was found in the synovial infiltrate and at sites of focal bone erosion, using specific immunohistochemistry. Interestingly, AdIL-17 not only enhanced RANKL expression but also strongly up-regulated the RANKL/OPG ratio in the synovium. Comparison of arthritic mice from the AdIL-17 collagen-induced arthritis group with full-blown collagen-arthritic mice having similar clinical scores for joint inflammation revealed lower RANKL/OPG ratio and tartrate-resistant acid phosphatase activity in the latter group. Interestingly, systemic OPG treatment prevented joint damage induced by local AdIL-17 gene transfer in type 11 collagen-immunized mice. These findings suggest T cell IL-17 to be an important inducer of RANKL expression leading to loss of the RANKL/OPG balance, stimulating osteoclastogenesis and bone erosion in arthritis.