After Blocking Estrogen Signals in Brain, Experts Say They’ve ‘Never Seen Bone This Strong’
A handful of brain cells deep in the brain may play a surprising role in controlling women’s bone density, according to new research by UC San Francisco and UCLA scientists.
In a study published January 11, 2019 in Nature Communications, researchers showed 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.
“Our collaborators who study bone for a living said they’d never seen bone this strong,” said study senior author Holly Ingraham, PhD, who is professor and vice-chair of cellular and molecular pharmacology and Herzstein Distinguished Investigator in Molecular Physiology at UCSF. “Our current understanding of how the body controls bone growth can’t explain this, which suggests we may have uncovered a completely new pathway that could be used to improve bone strength in older women and others with fragile bones.”
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 one in three post-menopausal women in the US and Europe suffer from weakened bones) because of declining levels of the sex hormone estrogen, which normally promotes bone growth.
Estrogen plays many roles in the female body, particularly in the regulation of reproduction, but its function in the brain is still poorly understood. The Ingraham lab has 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.
Their new study began when Stephanie Correa, PhD, then an Ingraham lab postdoctoral researcher and now an assistant professor at UCLA, 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. Correa 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 percent.
“I was immediately struck by the size of the effect. The two groups didn’t overlap at all, which I had never seen,” Correa said. “We knew right away it was a game changer and a new, exciting direction with potential applications for improving women’s health.”
The mutant animals’ extra-dense bones also proved to be super-strong. When collaborators such as UCSF’s Aaron Fields, PhD, an assistant professor in the Department of Orthopedic Surgery, tested the mechanical strength of these bones by crushing them, his equipment almost failed, Ingraham says.
After Correa moved to UCLA, Ingraham lab postdoctoral fellows Candice Herber, PhD, and William Krause, PhD, 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. 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. “Most neuroscientists limit studies to male mice, and few study estrogen, which may explain why this had never been seen before,” Ingraham said. “I’ve always been interested in how sex hormones make male and female brains different, and this is a really wonderful example of how dramatic those differences can be.”
Further experiments showed that Ingraham and Correa’s 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, Herber and Krause were even able to reverse existing bone degeneration in an experimental model of osteoporosis. In female mice that had already lost more than 70 percent of their bone density due to experimentally lowered blood estrogen, deletion of arcuate estrogen receptors caused bone density to rebound by 50 percent 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, Ingraham said. “We 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 weakened bones as we age.”
The dramatic pattern of enhanced bone growth seen in the current study is unlike anything in the scientific literature, the researchers say, suggesting that Correa’s fortuitous discovery may have uncovered a totally novel biological pathway by which the brain regulates bone density. Ingraham and colleagues are now investigating exactly how this brain–bone communication happens, and whether drugs could be developed to boost bone strength in post-menopausal women without potentially dangerous effects of estrogen replacement therapy.
“This new pathway holds great promise because it allows the body to shift new bone formation into overdrive,” Correa said.
“I’m in the clouds about this result,” Ingraham added. “If our next experiments show that the brain releases a novel circulating factor that triggers enhanced bone growth, we might have a real chance of developing a drug that counteracts osteoporosis.”
The Latest on: Osteoporosis
via Google News
The Latest on: Osteoporosis
- Diabetes tied to increased risk of hidden spinal fractureson November 14, 2019 at 2:02 pm
These fractures can be caused by injuries or by osteoporosis and may have few symptoms, but they can lead to problems like severe chronic pain or reduced height. The current study included data from ...
- Julien Macdonald to host The Royal Osteoporosis Society fashion showon November 14, 2019 at 5:34 am
The 48-year-old fashion designer will present the gala dinner and catwalk at the glamorous event on November 27, which hopes to raise £300,000 to support research to find a cure for osteoporosis. The ...
- Osteoporosis: Here’s how you can prevent the conditionon November 14, 2019 at 5:06 am
Osteoporosis can't be cured but it can be prevented. Osteoporosis means porous bones, a condition in which the density and quality of the bones get impact. If your bones are porous, you are at an ...
- Osteoporosis: Not just an old person’s problemon November 13, 2019 at 10:29 am
This is because progressive bone depletion has made their bones too weak to tolerate even a slight injury. High risk of fractures is a major concern for people living with osteoporosis. Once a patient ...
- Osteoporosis Treatment Market Global Trends, Emerging Regions, Growth Factors, Share and Forecast by 2026on November 13, 2019 at 3:49 am
Nov 13, 2019 (The Expresswire) -- Osteoporosis Treatment Market Witness Lucrative Opportunities in North America Due to High Prevalence of Disease in the Region. Changing lifestyle and rising ...
- Postmenopausal Osteoporosis Drugs Market: Huge Growth Opportunities and Challenges to Watch in 2019on November 12, 2019 at 6:09 am
Nov 12, 2019 (Global QYResearch via COMTEX) -- Ameco Research in its report titled, "Postmenopausal Osteoporosis Drugs Market Analysis 2019 - Projections Report 2026," offers comprehensive insights ...
- Rose Fitness & Wellness: Osteoporosison November 11, 2019 at 5:41 am
Did you know that osteoporosis- which causes progressive bone deterioration- strikes men as well as women? The National Osteoporosis Foundation estimates that osteoporosis-related fractures ...
- Postmenopausal Osteoporosis reference genes for qPCR expression assayson November 11, 2019 at 2:21 am
Osteoporosis (OP) is a multifactorial disease, characterized by low bone mineral density (BMD) and loss of tissue microarchitecture 1,2,3. The disease is influenced by genetic factors in around 50-85% ...
- Who is most at risk of osteoporosis?on November 10, 2019 at 3:51 pm
Specialist doctor Shreerang Madhusudan Joshi says: “Women around the age of menopause and all older people including men above the age of 60 are most vulnerable to osteoporosis ... Being female puts ...
- Here’s how you can prevent osteoporosis in 5 stepson November 7, 2019 at 9:52 pm
So it’s only fair that the healthy practices one adopts also need a makeover. According to the International Osteoporosis Foundation: “Osteoporosis causes bones to become weak and fragile, so that ...
via Bing News