Bone – NIH Director's Blog (original) (raw)
Maternal Brain Hormone Key to Strengthening Bones Could Help Treat Osteoporosis, Bone Fractures
Posted on August 1st, 2024 by Dr. Monica M. Bertagnolli
Credit: Donny Bliss/NIH
More than 200 million people around the world have osteoporosis, a condition that weakens bones to the point that they break easily. Women are at especially high risk after menopause due to declining levels of the hormone estrogen, which helps keep bones strong. While osteoporosis rarely has noticeable symptoms, it can lead to serious injuries when otherwise minor slips and falls cause broken bones that in turn can lead to further fracture risk and fracture-related mortality. So, I’m pleased to share NIH-supported research suggesting a surprising candidate for strengthening bones: a maternal hormone produced in the brain.
The study in mice reported in Nature shows that this newly discovered hormone maintains and rebuilds bone strength in lactating females, even as estrogen levels dip and calcium is lost to the demands of milk production. 1 The findings suggest this hormone—or a drug that acts similarly—could be key to treating osteoporosis and preventing and healing broken bones.
The findings come from a team led by Holly Ingraham, University of California, San Francisco. The researchers knew from studies in mice and humans that a protein related to parathyroid hormone, which is made in the mammary glands, is the main driver for stripping calcium from maternal bones for milk production. As a result of this process, nursing mothers tend to lose a lot of bone. In humans, this bone loss is 10% on average, compared to nearly 30% in mice. Fortunately, these losses are reversed after lactation ends, suggesting to the researchers there must be some other bone-strengthening factor in play.
Previous work in Ingraham’s lab, also supported by NIH, offered other clues. The researchers found that in female mice, blocking a certain estrogen receptor in select neurons in a small area of the brain led to the development of bones that were exceptionally dense and strong. 2 This was an early hint that an unidentified hormone might have a role. The team’s search in this latest study led them to brain-derived communication network factor 3 (CCN3).
The new findings showed that, in lactating female mice, CCN3 is produced in the same brain area identified in the previous study. When the researchers prevented the brain from making CCN3, lactating female mice rapidly lost bone. The researchers also found that male and female young adult and older mice gained a considerable amount of bone mass and strength when their levels of circulating CCN3 were boosted over a two-week period. In fact, in some female mice that were very old or completely lacked estrogen, the hormone more than doubled their bone mass. Tests showed that the animals’ bones weren’t just denser, but also stronger.
Further studies conducted by co-author Thomas Ambrosi, University of California, Davis, revealed that bone stem cells were responsible for receiving signals and generating the new bone. When those cells were exposed to CCN3, they ramped up bone production even more. When the researchers applied a hydrogel patch containing CCN3 to the sites of bone breaks, this spurred the formation of new bone. As a result, the researchers saw rapid bone healing in older mice comparable to what would be expected in much younger mice.
In future studies, the researchers want to gain insight into the underlying mechanisms of CCN3. They also plan to explore the hormone’s potential for treating bone loss in people at increased risk, including postmenopausal women, breast cancer survivors taking estrogen blockers, and those with other conditions leading to unhealthy bone mass, such as genetic bone disorders, chronic kidney disease, or premature ovarian failure. They suggest that more immediate local uses for CCN3 include fracture repair, cartilage regeneration, and bone improvements for anchoring dental implants. It’s a great example of how finding an answer to a scientific puzzle—like how maternal bones stay strong during breastfeeding—can potentially lead to advances that help many more people.
References:
[1] Babey ME, et al. A maternal brain hormone that builds bone. Nature. DOI: 10.1038/s41586-024-07634-3 (2024).
[2] Herber CB, et al. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nature Communications. DOI: 10.1038/s41467-018-08046-4 (2019).
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Posted In: Health, Science, Uncategorized
Tags: aging, basic research, Bone, bone fracture, breastfeeding, calcium, estrogen, hormone, maternal health, menopause, osteoporosis
‘Exercise Hormone’ Tied to Bone-Strengthening Benefits
Posted on December 18th, 2018 by Dr. Francis Collins
Credit: gettyimages/kali9
There’s no doubt that exercise is good for us—strengthening our muscles, helping us maintain a healthy weight, maybe even boosting our moods and memories. There’s also been intriguing evidence that exercise may help build strong bones.
Now, an NIH-funded study is shedding light on the mechanism behind exercise’s bone-strengthening benefits [1]. The new work—which may lead to new approaches for treating osteoporosis, a disease that increases the risk of bone fracture—centers on a hormone called irisin that is secreted by muscles during exercise.
In a series of mouse experiments, the researchers found that irisin works directly on a common type of bone cell, stimulating the cells to produce a protein that encourages bones to thin. However, this chain of molecular events ultimately takes a turn for the better and reverses bone loss.
Bruce Spiegelman’s lab at the Dana-Farber Cancer Institute and Harvard University Medical School, Boston, first discovered the irisin hormone in 2012 [2]. In the years since, evidence has accumulated suggesting a connection between irisin and many of the benefits that come with regular workouts. For example, delivering low doses of irisin—sometimes called “the exercise hormone”—increase bone density and strength in mice.
But how does irisin act on bones? The answer hasn’t been at all clear. A major reason is the protein receptor on our cells that binds and responds to irisin wasn’t known.
In the new study reported in the journal Cell, Spiegelman’s team has now identified irisin’s protein receptor, called αVβ5 integrin. Those receptors are present on the surface of osteocytes, the most common cell type found in mature bone tissue.
The researchers went on to show that irisin helps osteocytes to live longer. It also leads the bone cells to begin secreting a protein called sclerostin, known for its role in preparing bones for remodeling and rebuilding by first breaking them down. Interestingly, previous studies also showed sclerostin levels increase in response to the mechanical stresses that come with exercise.
To further explore the role of irisin in mouse studies, the researchers gave the animals the hormone for six days. And indeed, after the treatment, the animals showed higher levels of sclerostin in their blood.
The findings suggest that irisin could form the basis of a new treatment for osteoporosis, a condition responsible for almost nine million fractures around the world each year. While it might seem strange that a treatment intended to strengthen bone would first encourage them to break down, this may be similar to the steps you have to follow when fixing up a house that has weakened timbers. And Spiegelman notes that there’s precedent for such a phenomenon in bone remodeling—treatment for osteoporosis, parathyroid hormone, also works by thinning bones before they are rebuilt.
That said, it’s not yet clear how best to target irisin for strengthening bone. In fact, locking in on the target could be a little complicated. The Speigelman lab found, for example, that mice prone to osteoporosis following the removal of their ovaries were paradoxically protected from weakening bones by the inability to produce irisin.
This new study fits right in with other promising NIH-funded efforts to explore the benefits of exercise. One that I’m particularly excited about is the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which aims to develop a comprehensive map of the molecular changes that arise with physical activity, leading to a range of benefits for body and mind.
Indeed, the therapeutic potential for irisin doesn’t end with bone. In healthy people, irisin circulates throughout the body. In addition to being produced in muscle, its protein precursor is produced in the heart and brain.
The hormone also has been shown to transform energy-storing white fat into calorie-burning brown fat. In the new study, Spiegelman’s team confirms that this effect on fat also depends on the very same integrin receptors present in bone. So, these new findings will no doubt accelerate additional study in Speigelman’s lab and others to explore the many other benefits of irisin—and of exercise—including its potential to improve our moods, memory, and metabolism.
References:
[1] Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM. Cell. 2018 Dec 13;175(7):1756-1768.
[2] A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. Nature. 2012 Jan 11;481(7382):463-8.
Links:
Posted In: News
Tags: aging, Bone, bone remodeling, exercise, exercise hormone, fat, irisin, memory, metabolism, Molecular Tranducers of Physical Activity Consortium, mood, MoTrPAC, muscle, osteocyte, osteoporosis, sclerostin, thinning bones
Halloween Fly-Through of a Mouse Skull
Posted on October 25th, 2018 by Dr. Francis Collins
https://directorsblog.nih.gov/wp-content/uploads/2018/10/Halloween2018.mp4
Credit: Chai Lab, University of Southern California, Los Angeles
Halloween is full of all kinds of “skulls”—from spooky costumes to ghoulish goodies. So, in keeping with the spirit of the season, I’d like to share this eerily informative video that takes you deep inside the real thing.
Posted In: Cool Videos
Tags: birth defects, Bone, cleft lip, cleft palate, craniofacial, craniofacial biology, craniosynostosis, development, face, FaceBase, FaceBase Consortium, Halloween, mouse, skull, virtual reality
Putting Bone Metastasis in the Spotlight
Posted on September 13th, 2018 by Dr. Francis Collins
When cancers spread, or metastasize, from one part of the body to another, bone is a frequent and potentially devastating destination. Now, as you can see in this video, an NIH-funded research team has developed a new system that hopefully will provide us with a better understanding of what goes on when cancer cells invade bone.
In this 3D cross-section, you see the nuclei (green) and cytoplasm (red) of human prostate cancer cells growing inside a bioengineered construct of mouse bone (blue-green) that’s been placed in a mouse. The new system features an imaging window positioned next to the new bone, which enabled the researchers to produce the first series of direct, real-time micrographs of cancer cells eroding the interior of bone.
Posted In: Cool Videos
Tags: Bone, bone metastasis, breast cancer, cancer, cancer imaging, imaging, iMPM, intravital multiphoton microscopy, metastases, metastatic cancer, mets, osteoclast, prostate cancer, tissue engineering, translational medicine, zoledronic acid
Cool Videos: The Ghost in the Lab Dish?
Posted on October 26th, 2017 by Dr. Francis Collins
As Halloween approaches, lots of kids and kids-at-heart will be watching out for ghosts and goblins. So, to help meet the seasonal demand for scary visuals, I’d like to share this award-winning image that’s been packaged into a brief video.
The “ghoul” you see above is no fleeting apparition: it’s a mouse cell labelled to reveal its microtubules, which are dynamic filaments involved in cellular structure, transport, and motility. Graduate student Victor DeBarros captured this image a couple of years ago in the NIH-supported lab of Randall Duncan at the University of Delaware, Newark, as part of research on the rare skeletal disorder metatropic dysplasia (MD).
Posted In: Health, Science, Video
Tags: art, Bone, cartilage, chondrocytes, Halloween, metatropic dysplasia, microtubules, musculoskeletal disorder, rare disease, skeletal disoder, translational science, TRPV4, University of Delaware Science as Art
Stem Cell Research: New Recipes for Regenerative Medicine
Posted on July 19th, 2016 by Dr. Francis Collins
Caption: From stem cells to bone. Human bone cell progenitors, derived from stem cells, were injected under the skin of mice and formed mineralized structures containing cartilage (1-2) and bone (3).
Credit: Loh KM and Chen A et al., 2016
To help people suffering from a wide array of injuries and degenerative diseases, scientists and bioengineers have long dreamed of creating new joints and organs using human stem cells. A major hurdle on the path to achieving this dream has been finding ways to steer stem cells into differentiating into all of the various types of cells needed to build these replacement parts in a fast, efficient manner.
Now, an NIH-funded team of researchers has reported important progress on this front. The researchers have identified for the first time the precise biochemical signals needed to spur human embryonic stem cells to produce 12 key types of cells, and to do so rapidly. With these biochemical “recipes” in hand, researchers say they should be able to generate pure populations of replacement cells in a matter of days, rather than the weeks or even months it currently takes. In fact, they have already demonstrated that their high-efficiency approach can be used to produce potentially therapeutic amounts of human bone, cartilage, and heart tissue within a very short time frame.
Tags: bioengineering, Bone, cartilage, development, embryonic stem cell, heart cells, human embryonic stem cell, mesoderm, muscle cells, regenerative medicine, replacement tissue, RNA sequencing, scoliosis, stem cell differentiation, stem cells, tissue engineering
Snapshots of Life: Inside a Bone Remodeling Project
Posted on November 6th, 2014 by Dr. Francis Collins
Caption: Osteoclast cells (red) carve a path through a knee joint (purple and white), enabling a blood vessel to supply the cells (yellow) needed to build new bone.
Credit: Paul R. Odgren, University of Massachusetts Medical School
Bones are one of our body’s never-ending remodeling projects. Specialized cells, called osteoclasts, are constantly attaching to old bone and breaking it down, using acids to dissolve the calcium. In the wake of this demolition, bone-building cells, called osteoblasts, move in and deposit new minerals to patch and remodel the bone, maintaining its strength and durability.
Normally, these two types of cells strike a delicate balance between bone destruction and formation. But if this balance goes awry, it can lead to trouble. With osteoporosis, for example, bone removal exceeds formation, yielding progressively weaker bones that are prone to fracture.
Promoting the Long Term Marriage of Bone and Implant
Posted on July 18th, 2013 by Dr. Francis Collins
Caption: Here we see the host bone (red and blue) growing in a cavity of the implant (brown and sliver). A new coating on the implant encourages this stable bond.
Credit: The Hammond Research Group, David H. Koch Institute of Integrative Cancer Research at MIT
Hip, knee, and shoulder joints get worn over time, or damaged by disease or injury. They often require replacement because they cause pain and inhibit movement. Orthopedic surgeons perform more than 1 million joint replacements each year. The worn bone is replaced with plastic or metal implants and cemented in place. The surgery can provide immense relief and restore mobility. But sometimes these implants don’t integrate well with the bone, and ultimately they break free. Replacement surgeries are costly, increase the risk of infection, and are a major challenge for the patient to endure. But recently an NIH-funded team of chemical engineers at MIT developed a special coating for implants that promotes a stronger connection to new bone.