Bones make hormones that communicate with the brain and other organs

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Long typecast as the strong silent type, bones are speaking up.

In addition to providing structural support, the skeleton is a versatile conversationalist. Bones make hormones that chat with other organs and tissues, including the brain, kidneys and pancreas, experiments in mice have shown.

“The bone, which was considered a dead organ, has really become a gland almost,” says Beate Lanske, a bone and mineral researcher at Harvard School of Dental Medicine. “There’s so much going on between bone and brain and all the other organs, it has become one of the most prominent tissues being studied at the moment.”

At least four bone hormones moonlight as couriers, recent studies show, and there could be more. Scientists have only just begun to decipher what this messaging means for health. But cataloging and investigating the hormones should offer a more nuanced understanding of how the body regulates sugar, energy and fat, among other things.

Of the hormones on the list of bones’ messengers — osteocalcin, sclerostin, fibroblast growth factor 23 and lipocalin 2 — the last is the latest to attract attention. Lipocalin 2, which bones unleash to stem bacterial infections, also works in the brain to control appetite, physiologist Stavroula Kousteni of Columbia University Medical Center and colleagues reported in the March 16 Nature.

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Bone-brain connection

After mice eat, their bone-forming cells absorb nutrients and release a hormone called lipocalin 2 (LCN2) into the blood. LCN2 travels to the brain, where it gloms on to appetite-regulating nerve cells, which tell the brain to stop eating, a recent study suggests.

Researchers previously thought that fat cells were mostly responsible for making lipocalin 2, or LCN2. But in mice, bones produce up to 10 times as much of the hormone as fat cells do, Kousteni and colleagues showed. And after a meal, mice’s bones pumped out enough LCN2 to boost blood levels three times as high as premeal levels. “It’s a new role for bone as an endocrine organ,” Kousteni says.

Clifford Rosen, a bone endocrinologist at the Center for Molecular Medicine in Scarborough, Maine, is excited by this new bone-brain connection. “It makes sense physiologically that there are bi­directional interactions” between bone and other tissues, Rosen says. “You have to have things to regulate the fuel sources that are necessary for bone formation.”

Bones constantly reinvent themselves through energy-intensive remodeling. Cells known as osteoblasts make new bone; other cells, osteoclasts, destroy old bone. With such turnover, “the skeleton must have some fine-tuning mechanism that allows the whole body to be in sync with what’s happening at the skeletal level,” Rosen says. Osteoblasts and osteoclasts send hormones to do their bidding.

Scientists began homing in on bones’ molecular messengers a decade ago (SN: 8/11/07, p. 83). Geneticist Gerard Karsenty of Columbia University Medical Center found that osteocalcin — made by osteoblasts — helps regulate blood sugar. Osteocalcin circulates through the blood, collecting calcium and other minerals that bones need. When the hormone reaches the pancreas, it signals insulin-making cells to ramp up production, mouse experiments showed. Osteocalcin also signals fat cells to release a hormone that increases the body’s sensitivity to insulin, the body’s blood sugar moderator, Karsenty and colleagues reported in Cell in 2007. If it works the same way in people, Karsenty says, osteocalcin could be developed as a potential diabetes or obesity treatment.

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Odd jobs

Bones produce hormones that go to work in other organs. Some of those functions are known, but researchers are finding new ways these hormones may work.

Hormone Function Proposed function Site of proposed activity
Lipocalin 2 (LCN2) Stops the spread of bacterial invaders Regulates appetite Brain
Osteocalcin Regulates bone mineralization and calcium metabolism Regulates:

Blood sugar and
insulin metabolism

Memory and mood

Testosterone
production

Pancreas and fat tissue

Brain

Testicles

Sclerostin Keeps bone growth in check Implicated in energy metabolism Fat tissue

“Their data is fairly convincing,” says Sundeep Khosla, a bone biologist at the Mayo Clinic in Rochester, Minn. “But the data in humans has been less than conclusive.” In observational studies of people, it’s hard to say that osteocalcin directly influences blood sugar metabolism when there are so many factors involved.

More recent mouse data indicate that osteocalcin may play a role in energy metabolism. After an injection of the hormone, old mice could run as far as younger mice. Old mice that didn’t receive an osteocalcin boost ran about half as far, Karsenty and colleagues reported last year in Cell Metabolism. As the hormone increases endurance, it helps muscles absorb more nutrients. In return, muscles talk back to bones, telling them to churn out more osteocalcin.

There are hints that this feedback loop works in humans, too. Women’s blood levels of osteocalcin increased during exercise, the team reported.

Mounting evidence from the Karsenty lab suggests that osteocalcin also could have more far-flung effects. It stimulates cells in testicles to pump out testosterone — crucial for reproduction and bone density — and may also improve mood and memory, studies in mice have shown. Bones might even use the hormone to talk to a fetus’s brain before birth. Osteocalcin from the bones of pregnant mice can penetrate the placenta and help shape fetal brain development, Karsenty and colleagues reported in 2013 in Cell. What benefit bones get from influencing developing brains remains unclear.

Another emerging bone messenger is sclerostin. Its day job is to keep bone growth in check by telling bone-forming osteoblasts to slow down or stop. But bones may dispatch the hormone to manage an important fuel source — fat. In mice, the hormone helps convert white (or “bad”) fat into more useful energy-burning beige fat, molecular biologist Keertik Fulzele of Boston University and colleagues reported in the February Journal of Bone and Mineral Research.

Osteocalcin, sclerostin and LCN2 offer tantalizing clues about bones’ communication skills. Another hormone, fibroblast growth factor 23, or FGF-23, may have more immediate medical applications.

Bones use FGF-23 to tell the kidneys to shunt extra phosphate that can’t be absorbed. In people with kidney failure, cancer or some genetic diseases, including an inherited form of rickets called X-linked hypophosphatemia, FGF-23 levels soar, causing phosphate levels to plummet. Bones starved of this mineral become weak and prone to deformities.

In the case of X-linked hypophosphatemia, or XLH, a missing or broken gene in bones causes the hormone deluge. Apprehending the molecular accomplice may be easier than fixing the gene.

In March, researchers, in collaboration with the pharmaceutical company Ultragenyx, completed the first part of a Phase III clinical trial in adults with XLH — the final test of a drug before federal approval. The scientists tested an antibody that latches on to extra FGF-23 before it can reach the kidneys. Structurally similar to the kidney proteins where FGF-23 docks, the antibody is “like a decoy in the blood,” says Lanske, who is not involved in the trial. Once connected, the duo is broken down by the body.

Traditionally, treating XLH patients has been like trying to fill a bathtub without a plug. “The kidney is peeing out the phosphorus, and we’re pouring it in the mouth as fast as we can so bones mineralize,” says Suzanne Jan De Beur, a lead investigator of the clinical trial and director of endocrinology at Johns Hopkins Bayview Medical Center. Success is variable, and debilitating side effects often arise from long-term treatment, she says. The antibody therapy should help restore the body’s ability to absorb phosphate.

Unpublished initial results indicate that the antibody works. Of 68 people taking the drug in the trial, over 90 percent had blood phosphate levels reach and stay in the normal range after 24 weeks of treatment, Ultragenyx announced in April. People taking the antibody also reported less pain and stiffness than those not on the drug.

Osteocalcin, sclerostin and LCN2 might also be involved in treating diseases someday, if results in animals apply to people.

In the study recently published in Nature, Kousteni’s team found that boosting LCN2 levels in mice missing the LCN2 gene tamed their voracious feeding habits. Even in mice with working LCN2 genes, infusions of the hormone reduced food intake, improved blood sugar levels and increased insulin sensitivity.

Researchers traced the hormone’s path from the skeleton to the hypothalamus — a brain structure that maintains blood sugar levels and body temperature and regulates other processes. Injecting LCN2 into mice’s brains suppressed appetite and decreased weight gain. Once the hormone crosses the blood-brain barrier and reaches the hypothalamus, it attaches to the surface of nerve cells that regulate appetite, the team proposed.

Mice with defective LCN2 docking stations on their brain cells, however, overate and gained weight just like mice that couldn’t make the hormone in the first place. Injections of LCN2 didn’t curb eating or weight gain.

(Two mouse studies by another research group published in 2010, however, found that LCN2 had no effect on appetite. Kousteni and colleagues say that inconsistency could have resulted from a difference in the types of mice that the two groups used. Additional experiments by Kousteni’s lab still found a link between LCN2 and appetite.)

In a small group of people with type 2 diabetes, those who weighed more had less LCN2 in their blood, the researchers found. And a few people whose brains had defective LCN2 docking stations had higher blood levels of the hormone.

If the hormone suppresses appetite in people, it could be a great obesity drug, Rosen says. It’s still too early, though, to make any definitive proclamations about LCN2 and the other hormones’ side hustles, let alone medical implications. “There’s just all sorts of things that we are uncovering that we’ve ignored,” Rosen says. But one thing is clear, he says: The era of bone as a silent bystander is over.



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