New target can help protect bones as we age


image: Dr Meghan McGee-Lawrence
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Credit: Michael Holahan, Augusta University

AUGUSTA, Georgia. (January 5, 2022) – Drugs we take like prednisone can weaken our bones, just like aging, and scientists working to prevent both have some of the first evidence that the best target may not be the logical target.

They find that in aging bones, the mineralocorticoid receptor, best known for its role in regulating blood pressure, is a key factor in bone health, says Dr. Meghan E. McGee-Lawrence, biomedical engineer in the Department. of cell biology and anatomy. at the Georgia Medical College.

And drugs that block the receptor, like high blood pressure drugs spironolactone and eplerenone, can help protect bone cells, says McGee-Lawrence, corresponding author of the study in the Journal of Bone and Mineral Research.

Drugs like prednisone are glucocorticoids, which are best known for their role in reducing inflammation and suppressing the immune response, which is why they work so well for problems like irritable bowel syndrome and l ‘arthritis. But, like aging, they can also disrupt the continuing healthy dynamics of bone formation and destruction.

Our natural glucocorticoid levels increase with age, and bones, at least when we are young, have more glucocorticoid receptors than mineralocorticoid receptors. Glucocorticoids can actually cause stem cells to make osteoblastic osteoblasts, but it also causes those osteoblasts to store more fat, and too much fat in the bone, like anywhere on our body, is probably not. good and generally correlates with bone loss, McGee -Lawrence said.

Reducing the impact of glucocorticoid receptors therefore seemed like a logical way to protect bones.

Scientists at MCG were once surprised to find that loss of functional glucocorticoid receptors did not protect against bone loss in younger mice on a low-calorie diet. In fact, there was an increased accumulation of fat in the bone marrow and a worsening of osteoporosis.

This time, they were examining the impact of endogenous glucocorticoids in an aging model and found again that when the glucocorticoid receptor was blocked, older mice also had greater fat accumulation in the bone marrow and worsening of bone disease.

They also found that mice had smaller muscle mass, chose to move less than mice typically do, and had higher blood pressure.

Another surprise was that when they used drugs to inhibit the mineralocorticoid receptor, many problems were reversed.

“The only way we found to eliminate this osteoblast lipid storage was to inhibit the mineralocorticoid receptor with drugs,” she says, and luckily, due to the receptors’ clear role in blood pressure, there is already drugs that do.

“I think that means if we’re going to understand what these stress hormones, these endogenous glucocorticoids do, we can’t just think of signaling through a receptor,” says McGee-Lawrence. For older bones, she thinks the mineralocorticoid receptors may be a better target.

“We thought removing the glucocorticoid receptor would make it better, but it made it worse,” McGee-Lawrence said. “We believe the mineralocorticoid receptor may be a big part of what’s wrong with aging bones.”

Both receptors are members of the steroid receptor family, and mineralocorticoid receptors are believed to have equal affinity for mineralocorticoids and glucocorticoids. The signaling pathways may be different in younger and older individuals, she notes.

McGee-Lawrence and his colleagues already have evidence that bone expression of mineralocorticoid receptors increases, potentially significantly, with age. They have had mixed results on whether glucocorticoid receptors decline with age and further explore what is happening with both levels of receptors and learn more about the role of mineralocorticoid receptors in bone, in particular. aging bones.

“We want to know what might cause bone cells to change the receptors they express and how they respond to it,” she says. “But there are a lot of things that happen with aging. We know inflammation changes with aging, so there are a lot of different clues that could be causing these things to change. “

The whole body impact that they have seen from their manipulation of receptors, such as higher blood pressure due to the removal of the glucocorticoid receptor, is also proof of the importance of bones as an endocrine organ, she says.

“By altering glucocorticoid signaling in bone, not only are we seeing changes in bone, but we are seeing changes in fat, muscle, adrenal glands, physical activity,” she said. which means that something of the bone communicates with all. these other bodily systems, an emerging role for research in its field.

In fact, the increased presence of fat in the bone marrow seen in osteoporosis has made it also considered a metabolic disease of the bone, just like obesity, especially the excess weight around. size, is considered a metabolic disease. Increased fat in the bone marrow has been associated with disuse, such as spinal cord injury, a high fat diet, taking glucocorticoids, such as steroids, and aging.

While fat is a ready source of energy for bone cells, too much can hinder bone cell formation. Scientists do not yet know whether cells are no longer using fat or if they are getting more fat, or both; they know that the accumulation of fat in bone cells coincides with less bone production, she reiterates.

“We’re trying to figure out exactly why these things are wrong so that we can choose the right path forward for a treatment strategy,” she says.

There is a lot of evidence in people that the synthetic glucocorticoids we take in pill form or injections can impact the bones, creating an unhealthy imbalance between the amount of bone made and the amount broken down.

One of the goals of the research at MCG has been to examine the impact on bones of our endogenous glucocorticoids, the ones we make, a less explored area. For years, McGee-Lawrence and his colleagues have studied bone-forming osteoblasts, which like most cells do not function optimally with age.

But it may be that even synthetic glucocorticoids also work through these alternative receptors to damage bone, meaning that trying to prevent their damage may also mean a different target, she says, again noting that the path may change as the person ages.

Interestingly, some other tissues known to have a lot of mineralocorticoid receptors inactivate glucocorticoids, which bone cannot, but that perhaps compensates by not having many mineralocorticoid receptors, at least in patients. young, she said.

The adrenal gland makes both glucocorticoids and mineralocorticoids, which production becomes less well regulated with age.

The research was supported by the National Institute on Aging and the American Diabetes Association.

Read the full study.


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