Bone regulators moonlight in the brain as fever inducers

Study in mice suggests proteins could be source of post-menopausal hot flashes

Beauty may be only skin deep, but hot goes to the bone.

Proteins involved in breaking down bones are also part of the body’s thermostat, a new study shows. The proteins — a receptor called RANK and the protein that binds to it, called RANKL — turn up the heat to cause fever during infections and also help regulate daily temperature rhythms in female rodents, a study published in the Nov. 26 Nature shows.

And the proteins, which are involved in osteoporosis, may also be a source of the hot flashes that post-menopausal women experience.

Scientists already knew that RANK and RANKL team up to help tear down bones. That demolition is part of the normal maintenance of bones in the body and in pregnant women, it also helps free up calcium that in turn is used to solidify the baby’s bones. The proteins are also part of the signaling pathway that prompts lactation. After menopause, the bone remodeling system may take tearing down too seriously, resulting in osteoporosis. Large-scale clinical trials have recently shown that denosumab, an antibody directed against RANKL, can help protect bones.

But the skeleton isn’t the only place the protein pair works. Researchers had been surprised to find it in the brain, says Josef Penninger, an immunologist at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences in Vienna. No one had a clue what bone proteins were doing in the brain, but it was important to find out before potentially giving RANK blockers such as denosumab to millions of women as an osteoporosis therapy, Penninger says.

To find out what role the proteins might play in the brain, Reiko Hanada a member of Penninger’s research group, injected RANKL into the brains of rats and mice. The rodents stopped moving around and were hot to the touch, both indications of fever. Inhibiting RANKL reduced the animals’ fevers.

In the new study, the researchers traced the proteins to neurons and to glial cells called astrocytes in parts of the brain already known to be involved in regulating body temperature. From there, the team used some genetics tricks to remove RANK from only the astrocytes. Even after being injected with RANKL, the animals’ fevers were not as high.

These proteins also participate in the daily rise and fall of body temperature dictated by circadian rhythms — at least in female mice. The female mice genetically engineered to lack RANK in their brains had increased body temperatures during the animals’ normal daytime sleeping period, a time when their body temperatures usually dip. For humans, a similar dip in body temperature happens at night. Researchers couldn’t find any differences in daily body temperature fluctuations between normal male mice and male mice lacking RANK in their brains.

Body temperature regulation by RANK and RANKL depends on female sex hormones made by the ovaries, the study found. The researchers speculate that in humans, rapid changes in the two proteins’ activity might lead to hot flashes in post-menopausal women who have lost the steadying influence of estrogen.

“It’s really very provocative,” says Steven Teitelbaum, a bone cell biologist at Washington University School of Medicine in St. Louis. Denosumab antibodies are too large to get across the protective blood-brain barrier, but researchers should be cautious about making other, smaller molecules. “The clinical message here is that one should be careful of any RANKL blockers that cross the blood-brain barrier.”

The new study also suggests that the proteins play a similar role in inducing fever in humans and mice. Other researchers had previously found that two children in a Turkish family have mutations in the gene that encodes RANK, leading to osteopetrosis, a condition in which the bones become very dense and brittle. In the new study, Penninger and colleagues reviewed the children’s medical histories. Even though the children had been hospitalized for severe pneumonia, they had not developed the very high fevers children normally experience with such an infection.

But the finding that the children didn’t get fevers doesn’t necessarily confirm that the RANK system controls body temperature in people, Teitelbaum says. Those children and others with weakened bones and immune systems often don’t develop fevers in response to an infection. A lack of fever can actually make people sicker.

“Fever protects us. It’s not a bad thing. Fever is a good thing,” Teitelbaum says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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