Long cast as the strong silent type, bones aren’t as quiet as they once seemed. It turns out they have a lot to say. And the rest of the body appears to be listening.
Scientists knew that bones are not just rigid scaffolds to hold up and protect soft tissues. The bones themselves are ever-changing. Day in and out they’re destroying old cells and then creating new ones. This constant turnover, known as remodeling, keeps bones strong and healthy.
Hormones are naturally secreted chemicals. They act like long-range messengers within the body, instructing some tissue to take up some task — and at just the proper time. Several hormones, for instance, are key to directing the remodeling of bones. Emerging data now suggest that bones don’t just inform other bones about when to do something. Studies in mice show that bone hormones chat with a host of organs and tissues, including the brain, kidneys and pancreas.
“There’s so much going on between bone and brain and all the other organs,” says Beate Lanske. She is a bone and mineral researcher at the Harvard School of Dental Medicine in Boston, Mass. Bone was once considered a “dead organ,” she notes. No more. Their active release of chemical signals now suggest bones may actually resemble glands — the tissues that release hormones.
Clifford Rosen is an endocrinologist (En-doh-krin-OLL-oh-gizt) at Maine Medical Center in Scarborough. He studies how bone hormones affect health and disease. He says, “The skeleton must have some fine-tuning mechanism.” That, he adds, must be what “allows the whole body to be in sync with what’s happening at the skeletal level.”
Bones require a lot of energy as they constantly remodel themselves. Cells known as osteoblasts make new bone. Others, known as osteoclasts, destroy old bone. So it makes sense for bones “to have things to regulate the fuel sources that are necessary for bone formation,” Rosen notes. Osteoblasts and osteoclasts can use hormones for this.
He points to a recent demonstration in mice of a bone-brain link. Bones unleash the hormone lipocalin 2 (LCN2) to stem bacterial infections. But a study now shows that LCN2 also works in the brain to control hunger.
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After a meal, a mouse’s bone-forming cells absorb nutrients and release LCN2 into the bloodstream. This hormone now travels to the brain. There it gloms onto hunger-controlling nerve cells. They tell the brain to stop eating, Stavroula Kousteni explains. A physiologist, she works at Columbia University Medical Center in New York City.
She and her colleagues reported the new finding March 16 in Nature.
Researchers had thought fat cells made most LCN2. But in mice, bones produce up to 10 times as much of this hormone as fat cells do. After a meal, their bones pumped out enough LCN2 to boost blood levels of the hormone to triple what they had been before the meal. Concludes Kousteni, appetite control is “a new role for bone.”
At least three other bone hormones also talk to organs other than bone. These hormones are osteocalcin, sclerostin and fibroblast growth factor 23. Scientists have only begun to eavesdrop on the conversations bones are having with such other tissues. And that snooping suggests bone chatter can play a role in controlling how the body manages sugar, energy and fat.
Scientists began homing in a decade ago on the chemicals that bones release as their messages. Gerard Karsenty is a geneticist at Columbia University Medical Center. He has discovered many links between the bone-hormone osteocalcin and metabolism, which is how the body uses food to fuel its activities. In 2007, he reported that osteocalcin helps keep blood-sugar levels in a healthy range.
Osteocalcin circulates in the blood. There, it collects calcium and other minerals that bones need. At least in mice, when the hormone reaches the pancreas, it tells cells to ramp up production of another hormone: insulin. This is the hormone that the body uses to move sugar out of the bloodstream and into cells, where it can fuel activities.
That same bone hormone that ups insulin production also tells fat cells it’s time to release a hormone that increases the body’s sensitivity to insulin. Diabetes is a serious disease where the body either makes too little insulin or comes to ignore the presence of much of its insulin. If osteocalcin works the same way in people as it does in mice, Karsenty says, it could become a potential drug to treat diabetes or obesity.
“Their data is fairly convincing,” says Sundeep Khosla. He is a bone biologist at the Mayo Clinic in Rochester, Minn. “But the data in humans has been less than conclusive,” he adds. Many things can affect how the body manages blood sugar, he notes. In people, it has been hard to show whether osteocalcin is a major player.
Mouse data also suggest that osteocalcin may play a role in how the body uses food, its energy source. After an injection of the hormone, old mice can run as far as younger mice. Old mice that didn’t receive an osteocalcin boost ran only about half as far, Karsenty and his colleagues reported last year in Cell Metabolism. As the hormone increases endurance, it helps muscles absorb more nutrients. Muscles respond by telling bones to make more osteocalcin.
Karsenty’s group has found hints that this same effect seems to take place in people. For instance, women’s blood levels of osteocalcin increase during exercise, they note.
Rodent data from the Karsenty lab suggest osteocalcin can do even more. This bone hormone stimulates cells in the male reproductive organs to pump out testosterone. That’s a hormone crucial for strength, bone density and reproduction. It may also improve mood and memory.
Bones might even use the hormone to talk to the brain of a fetus in the womb. Osteocalcin from the bones of pregnant mice can penetrate the womb to help shape the developing brain. That’s something that Karsenty’s team reported four years ago in Cell. What benefit bones get from influencing developing brains remains unclear.
Keertik Fulzele is a molecular biologist at Boston University in Massachusetts. His team has turned up another bone messenger that may affect metabolism: sclerostin (Sklair-OS-tun). This hormone’s day job is to tell bone-forming cells to slow down or stop. But bones may also dispatch this hormone to manage fat, an important energy source. In mice, sclerostin helps convert white (or “bad”) fat into more useful energy-burning beige fat. Fulzele’s team reported this in the February 2017 issue of the Journal of Bone and Mineral Research.
The activity of yet one more bone hormone seems to show promise in understanding a perplexing health condition. That hormone: fibroblast (FY-bro-blast) growth factor 23.
Bones use this FGF-23 to help the kidneys regulate blood levels of phosphate. That’s a mineral that serves as a major building block of bones and teeth. If the body has more phosphate than the bones need, those bones release FGF-23. It informs the kidneys to trash the excess phosphate by excreting it in the urine. But in people with kidney failure, cancer or some genetic diseases, FGF-23 levels can soar when they shouldn’t. This mistakenly encourages the body to dump too much phosphate. Bones then weaken as they become starved of the mineral.
Suzanne Jan De Beur is an endocrinologist at Johns Hopkins Bayview Medical Center in Baltimore, Md. There, she is studying an inherited disease in which FGF-23 is a major player. Known as XLH, this genetic disease leads to soft bones. In XLH, a missing or broken gene in bones causes a flood of FGF-23. De Beur’s team is testing a way to soak up the extra hormone to keep a patient’s bones from becoming too soft.
A clinical trial is a way to test whether a new drug is safe and effective against a disease. In March, De Beur’s group completed the first part of such a trial in adults with XLH. As a Phase III trial, this type serves as one of the final tests to see if a drug is reliable and safe enough to get government approval for use in patients.
The scientists are working with the drug company Ultragenyx. That company’s drug latches onto extra FGF-23 before the hormone can reach the kidneys. The drug acts “like a decoy in the blood,” says Lanske, who is not involved in the trial. When FGF-23 runs into the drug, it mistakenly attaches to it instead of going to the kidneys. Once connected, the duo gets broken down by the body.
Traditionally, doctors have treated XLH patients by giving them extra phosphate, notes De Beur. But it’s like trying to fill a bathtub without a plug, she says. The kidneys are peeing it out about as fast as we can pour it in the mouth. No surprise: It doesn’t always work. Plus, long-term treatment can cause severe side effects.
The trial researchers hope the new drug will help restore the body’s ability to absorb phosphate. Unpublished data indicate it just may work. Of the 68 people who got the drug, at least 9 in every 10 had normal blood phosphate levels after six months of treatment. People taking the drug also reported less pain and stiffness than those not on the drug, Ultragenyx announced in April.
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Bones produce hormones that affect the activity of other organs. Some roles for these hormones are well known. Other new roles have only recently begun to emerge.
|Hormone||Known Function||Proposed functions||Site of proposed activity|
|Lipocalin 2 (LCN2)||Stops the spread of bacterial invaders||Regulates appetite||Brain|
|Osteocalcin||Regulates bone renewal and calcium use||Regulates:|
Blood sugar and
Memory and mood
Pancreas and fat tissue
|Sclerostin||Keeps bone growth in check||Plays role in food use by the body||Fat tissue|
If results in animals apply to people, osteocalcin, sclerostin and LCN2 might one day also be used to treat diseases.
In a recent study, Kousteni’s team found that boosting LCN2 levels in mice that lacked the LCN2 gene tamed their voracious feeding habits. Even in mice with working LCN2 genes, injecting them with extra amounts of this hormone made them eat less. It also lowered their blood sugar and increased their sensitivity to insulin. These last two traits suggest this hormone might one day be used to treat people with type 2 diabetes.
Researchers traced LCN2’s path from the bones to the brain’s hypothalamus (HY-poh-THAL-uh-mus). This part of the brain helps maintain healthy blood-sugar levels and body temperature. Injecting LCN2 into mice’s brains made them less hungry appetite and cut their weight gain. The hormone attaches to the surface of nerve cells that regulate appetite, the team now proposes.
To work, the LCN2 must insert itself into a receptor, or docking station, on brain cells. So mice whose cells had defective LCN2 docking stations responded differently. They ate too much. And they gained weight just like mice that couldn’t make the hormone in the first place. Injections of LCN2 didn’t curb their eating or weight gain.
Some early work suggests LCN2 may play a similar role in people with type 2 diabetes.
In a small group of patients, those who were overweight had less LCN2 in their blood. And a few people whose brains had defective LCN2 docking stations had higher blood levels of the bone hormone. This suggests LCN2 had nowhere to attach in the brain. So it built up in the blood.
If the hormone suppresses appetite in people, it could be a great obesity drug, Rosen says. But it’s too early to make any firm conclusions about its potential role as a medicine for people.
Yet one thing is clear, he says. The era of calling bone a silent bystander is over.
bacterial Having to do with bacteria, single-celled organisms. These dwell nearly everywhere on Earth, from the bottom of the sea to inside animals.
biology The study of living things. The scientists who study them are known as biologists.
blood sugar The body circulates glucose, a type of simple sugar, in blood to tissues of the body where it will be used as a fuel. The body extracts this simple sugar from breakdown of sugars and starches. However, some diseases, most notably diabetes, can allow an unhealthy concentration of this sugar to build up in blood.
bone remodeling The lifelong process of continually breaking down old bone cells and replacing them with healthy new ones.
calcium A chemical element which is common in minerals of the Earth’s crust and in sea salt. It is also found in bone mineral and teeth, and can play a role in the movement of certain substances into and out of cells.
cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. as yeasts, molds, bacteria and some algae, are composed of only one cell.
chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.
chemical signal A message made up of molecules that get sent from one place to another. Bacteria and some animals use these signals to communicate.
clinical trial A research trial that involves people.
colleague Someone who works with another; a co-worker or team member.
density The measure of how condensed some object is, found by dividing its mass by its volume.
diabetes A disease where the body either makes too little of the hormone insulin (known as type 1 disease) or ignores the presence of too much insulin when it is present (known as type 2 diabetes).
docking The act of bringing together and inserting one thing into another.
endocrinologist A doctor who specializes in conditions affecting the production of hormones or the body’s response to hormones.
fat A natural oily or greasy substance occurring in plants and in animal bodies, especially when deposited as a layer under the skin or around certain organs. Fat’s primary role is as an energy reserve. Fat also is a vital nutrient, though it can be harmful if consumed in excessive amounts.
fetus (Adj. fetal ) The term for a mammal during its later-stages of development in the womb. For humans, this term is usually applied after the eighth week of development.
fibroblast A type of cell found in connective tissue; it makes and releases proteins important in wound healing.
fuel Any material that will release energy during a controlled chemical reaction.
gene (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.
genetic Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.
gland A cell, a group of cells or an organ that produces and discharges a substance (or “secretion”) for use elsewhere in the body or in a body cavity, or for elimination from the body.
hormone (in zoology and medicine) A chemical produced in a gland and then carried in the bloodstream to another part of the body. Hormones control many important body activities, such as growth. Hormones act by triggering or regulating chemical reactions in the body.
hypothalamus A region of the brain that controls bodily functions by releasing hormones. The hypothalamus is involved in regulating appetite through release of appetite-suppressing hormones.
insulin A hormone produced in the pancreas (an organ that is part of the digestive system) that helps the body use glucose as fuel.
kidney Each in a pair of organs in mammals that filters blood and produces urine.
lipocalin 2 (LCN2) A hormone produced by bone that can help the body fight bacterial infections. Emerging data also indicate it may play a role in regulating appetite.
mechanism The steps or process by which something happens or “works.” Researchers often look for the mechanism behind actions and reactions to understand how something functions.
metabolism The set of life-sustaining chemical reactions that take place inside cells and bigger structures, such as organs. These reactions enable organisms to grow, reproduce, move and otherwise respond to their environments.
mineral Crystal-forming substances that make up rock, such as quartz, apatite or various carbonates. A mineral usually is solid and stable at room temperatures and has a specific formula, or recipe (with atoms occurring in certain proportions) and a specific crystalline structure (meaning that its atoms are organized in regular three-dimensional patterns). (in physiology) The same chemicals that are needed by the body to make and feed tissues to maintain health.
muscle A type of tissue used to produce movement by contracting its cells, known as muscle fibers. Muscle is rich in protein, which is why predatory species seek prey containing lots of this tissue.
nerve A long, delicate fiber that transmits signals across the body of an animal. An animal’s backbone contains many nerves, some of which control the movement of its legs or fins, and some of which convey sensations such as hot, cold or pain.
nutrient A vitamin, mineral, fat, carbohydrate or protein that a plant, animal or other organism requires as part of its food in order to survive.
obesity (adj. obese) Extreme overweight. Obesity is associated with a wide range of health problems, including type-2 diabetes and high blood pressure.
organ (in biology) Various parts of an organism that perform one or more particular functions. For instance, an ovary is an organ that makes eggs, the brain is an organ that makes sense of nerve signals and a plant’s roots are organs that take in nutrients and moisture.
osteoblast The type of cell used by the body to make new bone tissue.
osteoclast The type of cell that breaks down and removes old bone tissue.
osteocalcin A hormone produced by the bones. It plays a role in bone formation, the production of testosterone (the primary male reproductive hormone), and may influence mood and memory. In addition, emerging data suggest this hormone also may help control both blood-sugar and insulin levels in the body.
pancreas A gland found in animals with backbones that secretes the hormone insulin and enzymes that help break down foods in the gut.
phosphate A chemical containing one atom of phosphorus and four atoms of oxygen. It is a component of bones, hard white tooth enamel, and some minerals such as apatite.
physiologist A scientist who studies the branch of biology that deals with how the bodies of healthy organisms function under normal circumstances.
regulate (n. regulation) To control with actions. Governments write rules and regulations — laws — that are enforced by police and the courts.
reproductive organs The organs in a creature’s body that allows it to make and deliver eggs or sperm, and where appropriate, to nurture developing eggs and fetuses.
rodent A mammal of the order Rodentia, a group that includes mice, rats, squirrels, guinea pigs, hamsters and porcupines.
sclerostin A hormone produced by bone that not only keeps the rate of new bone formation under control. Emerging data indicate it also may play a role in helping determine whether the body used food as fuel or instead stores the calories in fat.
side effects Unintended problems or harm caused by a procedure or treatment.
sync Short for synchrony or synchronize. To work or move together in harmony and at the same time or rate, as in a marching band.
testosterone Although known as a male sex hormone, females make this reproductive hormone as well (generally in smaller quantities). It gets its name from a combination of testis (the primary organ that makes it in males) and sterol, a term for some hormones. High concentrations of this hormone contribute to the greater size, musculature and aggressiveness typical of the males in many species (including humans).
tissue Made of cells, any of the distinct types of materials that make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues.
trait A characteristic feature of something. (in genetics) A quality or characteristic that can be inherited.
type 2 diabetes (see also diabetes) A disease caused by the body’s inability to effectively use insulin, a hormone that helps the body process and use sugars. Unless diabetes is controlled, a person faces the risk of heart disease, coma or death.
womb Another name for the uterus, the organ in mammals in which a fetus grows and matures in preparation for birth.
XLH Short for X-linked hypophosphatemia, it’s an inherited disease that causes the kidneys to excete too much phosphate. That’s a mineral important for strong bones and teeth. People born with this condition develop rickets — weak and deformed bones. The condition is due to a gene mutation on the x-chromosome.
Journal: I. Mosialou et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. Vol. 543, March 16, 2017, p. 385. doi: 10.1038/nature21697.
Journal: K. Fulzele et al. Osteocyte-secreted Wnt signaling inhibitor sclerostin contributes to beige adipogenesis in peripheral fat depots. Journal of Bone and Mineral Research. Vol. 32, February 2017, p. 373. doi: 10.1002/jbmr.3001.
Journal: P. Mera et al. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metabolism. Vol. 23, June 14, 2016, p. 1078. doi: 10.1016/j.cmet.2016.05.004.
Journal: F. Oury et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell. Vol. 155, September 26, 2013, p. 228. doi: 10.1016/j.cell.2013.08.042.
Journal: K.J Oldknow, V.E. MacRae and C. Farquharson. Endocrine role of bone: recent and emerging perspectives beyond osteocalcin. Journal of Endocrinology. Vol. 225, April 1, 2015, p. R1. doi: 10.1530/JOE-14-0584.
Journal: F. Oury et al. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. Journal of Clinical Investigation. Vol. 123, June 3, 2013, p. 2421. doi: 10.1172/JCI65952.
Journal: N.K. Lee et al. Endocrine regulation of energy metabolism by the skeleton. Cell. Vol. 130, August 10, 2007, p. 456. doi: 10.1016/j.cell.2007.05.047.