RANK signaling is not required for TNFα-mediated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis
RANK signaling is not required for TNFα-mediated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis
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DOI：
10.1359/jbmr.0301233
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发表时间：
2004-02-01
影响因子：
6.2
通讯作者：
Xing, LP
中科院分区：
文献类型：
--
作者：
Li, P;Schwarz, EM;Xing, LP
简介：尽管TNF α在炎性关节炎中的关键作用和RANKL在骨吸收中的关键作用已经被牢固地确立，但关于TNF α在破骨细胞生成过程中可以补偿RANKL的程度以及破骨细胞生成所需RANK信号传导的阶段仍然存在中心争议。在此，我们使用侵蚀性关节炎的人TNF α转基因小鼠模型（TNF-Tg）来确定在TNF α诱导的侵蚀性关节炎中是否存在破骨细胞生成的RANK依赖性和非依赖性阶段。使用组织学、荧光激活细胞分选术（FACS）和细胞培养分析了（1）RANKL拮抗剂处理的TNF-Tg小鼠，RANK：Fc，或（2）TNF-Tg × RANK（-/-）小鼠，通过TNF-Tg小鼠与RANK（-/-）小鼠杂交产生。结果：用RANK：Fc治疗脾脏中OCP增加的TNF-Tg小鼠，显著减少关节炎关节表面和骨内的破骨细胞数量，但没有减少脾脏中CD 11b（hi）OCP数量。长期RANK：Fc给药缓解了关节侵蚀。此外，TNF-Tg X RANK（-/-）小鼠有严重的骨硬化症，没有破骨细胞，没有关节侵蚀，但增加的CD 11b（hi）前体数量，未能形成成熟的破骨细胞在vitro.Conclusion：RANK信号是必不可少的成熟破骨细胞的形成在TNFa-介导的炎性关节炎，但不是TNFa-诱导的增加CD 11b（hi）OCP，随后可以分化成破骨细胞在发炎的关节。
Introduction: Although critical roles of TNFalpha in inflammatory arthritis and RANKL in bone resorption have been firmly established, a central controversy remains about the extent to which TNFalpha can compensate for RANKL during osteoclastogenesis and the stage at which RANK signaling is required for osteoclastogenesis. Here, we used the human TNFalpha transgenic mouse model (TNF-Tg) of erosive arthritis to determine if there are both RANK-dependent and -independent stages of osteoclastogenesis in TNFalpha-induced erosive arthritis.Materials and Methods: Osteoclastogenesis and osteoclast precursor (OCP) frequency were analyzed using histology, fluorescence-activated cell sorting (FACS), and cell culture from (1) TNF-Tg mice treated with the RANKL antagonist, RANK:Fc, or (2) TNF-Tg X RANK(-/-) mice generated by crossing TNF-Tg mice with RANK(-/-) mice.Results: Treatment of TNF-Tg mice, which have increased OCPs in their spleens, with RANK:Fc dramatically reduced osteoclast numbers on the surface of their arthritic joints and within their bones, but did not decrease CD11b(hi) OCP numbers in their spleens. Long-term RANK:Fc administration alleviated joint erosion. Furthermore, TNF-Tg X RANK(-/-) mice had severe osteopetrosis, no osteoclasts, and no joint erosion, but increased CD11b(hi) precursor numbers that failed to form mature osteoclasts in vitro.Conclusion: RANK signaling is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis but not for the TNFalpha-induced increase in CD11b(hi) OCP that subsequently can differentiate into osteoclasts in inflamed joints.