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Moving the target for osteoporosis treatment

Medical College of Georgia at Augusta University

Dr. Carlos M. Isales, endocrinologist, has identified a major axis within the bone that regulates bone production and loss.

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A major axis that helps regulate the critical balance of bone production and loss has been found within bone cells, according to Medical College of Georgia researchers.

The finding provides a potential new target for treating debilitating osteoporosis and supports the evolving realization that most control of the constant cellular chatter that maintains healthy bone mass occurs in bone, not in the brain as previously believed, says Dr. Carlos M. Isales, endocrinologist.

"Probably the major component of bone regulation is local regulation," says Dr. Isales, who is presenting the findings at the 25th annual meeting of the American Society for Bone and Marrow Research Sept. 19-23 in Minneapolis.

He and colleagues at MCG, Yale University and the Department of Veterans Affairs Medical Center in Augusta have found that bone cells have all the components needed to regulate activity including a large molecule called POMC which makes a hormone called ACTH and its receptors.

ACTH was previously believed to exist mainly in the brain, where it regulates the adrenal gland's secretion of cortisol, another important hormone involved in maintaining blood pressure, electrolytes and blood sugar. "Cortisol is an important hormone for survival," says Dr. Isales. "It acts on the cell to stimulate production of a whole set of proteins that are important in cell survival and function. This was felt to be the main role for ACTH." Ironically, cortisol has a negative impact on bone, increasing bone-eating cells called osteoclasts and impairing calcium absorption.

But Dr. Isales and his colleagues serendipitously found ACTH is also secreted by osteoclasts and their bone-producing counterparts, osteoblasts, have ACTH receptors. And ACTH is very active within bone cells; in fact, his analysis of gene activity showed the expression of 714 genes was altered by ACTH.

"We now know it has multiple functions and one of them is making bone cells proliferate. One function we know is making them become more mature, so I think something activates osteoclasts, for example the loss of estrogen, and that makes osteoclasts more active at eating bone." But that also makes osteoclasts secrete ACTH, which makes bone-making osteoblasts more active to limit the damage resulting from estrogen loss. "That is how they talk to each other. I think it's a fail-safe mechanism for preventing the osteoclasts from eating through all the bone."

This release of a hormone next to a target cell is called paracrine, as opposed to endocrine, which means secretion of a hormone into the bloodstream for action at a distant site. "When you have paracrine function, it gives you much finer control, so you have these bone cells in close proximity acting on each other," Dr. Isales says.

Researchers in Japan recently described another local control system in the bone that prompts bone-eating osteoclasts, which work only in their mature state, to mature while osteoblasts are secreting a dummy receptor for the same ligand that prompts osteoclasts to reach maturity. "Basically the system always has one foot on the brake and one on the accelerator at the same time because bone is a very key tissue and you want it to be very tightly controlled," Dr. Isales said.

Before findings such as those at MCG began emerging, it was believed bone regulation was an endocrine function, that ACTH and other key substances journeyed from the brain to find and act on bone throughout the body.

The MCG finding could lead to development of ACTH analogues that specifically activate receptors in the bone, prompting bone production. But first the researchers are developing a mouse that lacks this receptor; Dr. Isales believes the mouse will have very thin bones and serve as proof of the new principal.

Current osteoporosis treatments, such as Fosamax, kill off osteoclasts in an effort to restore balance in patients who are losing more bone than they make; older treatments, such as hormone replacement therapy, are falling into disfavor because of potentially serious side effects.

Dr. Isales believes still more effective treatments with fewer side effects may be those that target the hormone cross talk now known to occur between bone cells.


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