蛋白RANK (receptor activator of nuclear factor κB)及其配体RANKL是必要的骨髓调控因子，针对RANKL的抗体作为骨质疏松症的治疗药物正在开发当中。RANKL 和 RANK也在中枢神经系统中表达，尽管其功能一直不清楚。

现在，用大鼠和小鼠所做研究表明，RANKL/RANK在大脑的星细胞中表达，而且令人吃惊的是，注射了RANKL的动物会严重发烧，而通过基因工程方法使星细胞不含RANK的小鼠则不会发烧。其他数据也表明，RANKL/RANK在炎症的中枢发烧反应和在雌性的体温控制中都扮演一个角色。有趣的是，对患有与RANK突变相关的骨质疏松症的两名儿童所做临川观察显示，在肺炎发病期间没有发烧。RANKL/RANK有可能是女性绝经期有时会出现的潮热或潮红中的相关因素。

Nature 462, 505-509 (26 November 2009) | doi:10.1038/nature08596

Central control of fever and female body temperature by RANKL/RANK

Reiko Hanada1, Andreas Leibbrandt1, Toshikatsu Hanada1, Shiho Kitaoka2, Tomoyuki Furuyashiki2, Hiroaki Fujihara3, Jean Trichereau1, Magdalena Paolino1, Fatimunnisa Qadri4, Ralph Plehm4, Steffen Klaere5, Vukoslav Komnenovic1, Hiromitsu Mimata6, Hironobu Yoshimatsu6, Naoyuki Takahashi7, Arndt von Haeseler5, Michael Bader4, Sara Sebnem Kilic8, Yoichi Ueta3, Christian Pifl9, Shuh Narumiya2 & Josef M. Penninger1

1 IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
2 Kyoto University Graduate School of Medicine, Department of Pharmacology, Kyoto 606-8501, Japan
3 Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan
4 Max Delbrueck Centre for Molecular Medicine, 13125 Berlin, Germany
5 Center of Integrated Bioinformatics, Max F. Perutz Laboratories, 1030 Vienna, Austria
6 Oita University Faculty of Medicine, Oita 879-5593, Japan
7 Institute for Oral Science, Matsumoto Dental University, Nagano 399-0781, Japan
8 Uludag University Medical Faculty, 16059 Bursa, Turkey
9 Medical University of Vienna, Center for Brain Research, 1090 Vienna, Austria
10 Correspondence to: Josef M. Penninger1 Correspondence and requests for materials should be addressed to J.M.P.

Receptor-activator of NF-B ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland1, 2, 3, 4. RANKL and RANK are also expressed in the central nervous system5, 6. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rankfloxed deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rankfloxed deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1 and TNF. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE2/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rankfloxed mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.