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

Bone protein link to fever The protein RANK (receptor-activator of nuclear factor κB) and its ligand RANKL are essential bone marrow regulators, and antibodies against RANKL are being developed as therapeutics in osteoporosis. RANKL and RANK are also expressed in the central nervous system, though their function there has been unclear. Studies in rats and mice now show that RANKL/RANK are expressed in astrocytes in the brain and that surprisingly, animals injected with RANKL develop severe fever, whereas genetically engineered mice with astrocytes lacking RANK are fever-resistant. Other data are consistent with a role for RANKL/RANK in both the central fever response in inflammation and in the control of female body temperature. Interestingly, clinical observations of two children with osteoporosis associated with RANK mutations revealed an absence of fever during bouts of pneumonia. It is possible that RANKL/RANK are factors in the hot flashes or flushes sometimes experienced by women during the menopause.