Researchers unlock mystery behind RANK and fever link
Mammals are ingenious creatures. An example of their ingenuity is how they have the capacity to control bone remodelling. The so-called RANK protein and the molecule that binds to it, the RANK ligand (RANKL), are key regulators of bone remodelling. Bones provide calcium to nursing mums, who in turn release calcium for their babies through their milk; and we come full circle. Researchers have discovered, however, that this system can also help control fever as well as female body temperature. The research was partially funded under an EU Marie Curie Excellence Grant, and an EU ERC Advanced Grant. The results were presented in the journal Nature. The researchers, led by Dr Josef Penninger at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), said that RANK and RANKL form the focus of Dr Penninger's work. Just a decade ago, Dr Penninger showed that the RANK/RANKL system was the 'master regulator' governing bone loss by deleting the RANKL gene from mice. The 1999 study offered the research world genetic proof for new and sound treatment for osteoporosis, a disease that primarily affects women. Meanwhile, clinical trials for a human antibody to RANKL have been published and experts believe that this antibody - pending approval by authorities - has the potential to be made available for treatment of this age-related bone disease. Thanks to Penninger's latest work, we have gained insight into how RANK and RANKL function. Until now, researchers were not aware of how they performed in the brain. Dr Reiko Hanada, an endocrinologist and member of Penninger's group, injected RANKL into mice and rats to determine whether any behavioural effects would emerge, as potential side effects could obstruct any benefits. 'In principle the injections could have resulted in changes to the animals' intelligence or memory or in subtle behavioural alterations that we could never have detected,' explained Dr Penninger. 'But we were lucky. The results were dramatic and obvious - the animals stopped moving and developed really high temperatures.' According to the researchers, the proteins were found to be limited to areas that other groups had previously implicated in the control of body temperature. Also, the results indicated that injections of RANKL produced changes in the areas of the brain that are linked to fever response, through which mammals boost their body temperature in order to fight infection. Contrary to how normal mice reacted, the mice that had been engineered to lack RANK in the brain did not respond to simulated infections by increasing their body temperature - but they seemed otherwise normal. So the research shows that RANK and its ligand play a key role in the regulation of the body's fever response to fight infections. Concerning female body temperature, the researchers speculated that the system might affect temperature because RANK and RANKL do control milk production during pregnancy. Dr Penninger and his group discovered that female mice lacking RANK in the brain registered a considerable increase in body temperature compared with their littermates in the daytime. The data also connect bone metabolism to temperature control during infection. Collaborating with the IMBA in this study were the Kyoto University Graduate School of Medicine, the University of Occupational and Environmental Health, the Oita University Faculty of Medicine, and the Institute for Oral Science of Matsumoto Dental University (all from Japan), the Max Delbrück Centre for Molecular Medicine (Germany), the Center of Integrated Bioinformatics, part of Max F. Perutz Laboratories (Austria), the Uludag University Medical Faculty (Turkey) and the Center for Brain Research of the Medical University of Vienna (Austria).