More than 200 million people worldwide suffer from osteoporosis, a weakening of the bones to the point where falls or even minor stresses like bending over or coughing can trigger fractures. In healthy individuals, bone tissue is constantly being recycled — old bone tissue is broken down and replaced by new bone. As we age, this cycle tilts in favor of bone loss, causing our bones to become increasingly porous and fragile. Women are at particularly high risk of osteoporosis after menopause (nearly 1 in 3 post-menopausal women in USA and Europe suffer from weakened bones) because of declining levels of the sex hormone estrogen, which normally promotes bone growth. Estrogens (mainly estradiol) plays many roles in the female body, particularly in the regulation of reproduction, but its function in the brain is still poorly understood. Several labs have long sought to understand how estrogen’s signaling in the brain impacts the female metabolism at different life stages, including how estrogen-sensitive neurons in a brain region called the hypothalamus balance energetic demands needed for survival or reproduction.
According to researches by UC San Francisco and UCLA scientists, a handful of brain cells deep in the brain may play a surprising role in controlling women’s bone density. Researchers have been able to prove that blocking a particular set of signals from these cells causes female (but not male) mice to build extraordinarily strong bones and maintain them into old age, raising hopes for new approaches to preventing or treating osteoporosis in older women. Their study began when they originally found that genetically deleting the estrogen receptor protein in hypothalamic neurons caused mutant animals to gain a little weight, and also to become less active. They expected to find that the animals had put on extra fat or gained lean muscle, but these did not explain the difference. To find the source of the extra weight, she decided to use an extra-sensitive laboratory technique that could also reveal changes in bone density. To her surprise, she discovered that her heavy mice were truly just big-boned: the animals’ bone mass had increased by as much as 800%.
Scientists were also shocked by the experimental works on bones. The mutant animals’ extra-dense bones proved to be super-strong. When researchers tested the mechanical strength of these bones by crushing them, their equipment almost failed. They therefore spearheaded a series of experiments that zeroed in on a specific population of just a few hundred estrogen-sensitive brain cells, located in a region of the hypothalamus called the arcuate nucleus, which appeared to be responsible for these dramatic increases in bone density. These neurons express a special neuropeptide called kisspeptin (Kiss-1). The authors hypothesized that estrogen must normally signal these neurons to shift energy away from bone growth, but that deleting the estrogen receptors had reversed that shift. Notably, interfering with arcuate estrogen signaling in male mice appeared to have no effect. They explains that neuroscientists limit studies to male mice, and few study estrogen, which may explain why this had never been seen before. Further experiments showed that mutant animals maintained their enhanced bone density well into old age.
Normal female mice begin to lose significant bone mass by 20 weeks of age, but mutant animals maintained elevated bone mass well into their second year of life, quite an old age by mouse standards. Remarkably, scientists were even able to reverse existing bone degeneration in an experimental model of osteoporosis. In female mice that had already lost more than 70% of their bone density due to experimentally lowered blood estrogen, deletion of arcuate estrogen receptors caused bone density to rebound by 50% in a matter of weeks. These results highlight the opposite roles played by estrogen in the blood, where it promotes bone stability, and in the hypothalamus, where it appears to restrain bone formation. Because dopaminergic neurons of the arcuate nucleus are modulated by Kiss-1, researchers are interested to determine how these two estrogen-responsive ARC modules communicate to coordinate female bone and energy metabolism before, during, and after pregnancy.
Beside pregnancy, the fact that dopamine and estradiol have a deep intercellular crosstalk, this enlarges the possibility to extend knowledge on the relationship between dopamine, depression and post-menopausal osteoporosis. The team hypothesize that after puberty the estrogen system in the female brain actively shifts resources away from bone growth and towards things like reproduction, which could contribute to women’s higher risk of osteoporosis as they age.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
van Veen JE et al. Nat Metab. 2020; 2(4):351-363.
Herber CB et al. Nat Commun. 2019;10(1):163.
Idelevich A et al. J Clin Invest. 2018; 128(6):2626.
Wee NK, Kulkarni RN et al. Bone 2016; 82:56-63.
Correa SM et al. Cell Rep. 2015 Jan; 10(1):62-74.