Researchers at the Washington University School of Medicine in St. Louis think they might be on the right trail to pinpoint the mechanism:
“High-dose cortisone is the second most common cause of osteoporosis, and we currently have no real treatment for this serious side effect,” says senior author Steven L. Teitelbaum, M.D., Messing Professor of Pathology and Immunology. “Given how frequently these drugs are used to treat many different conditions, that’s a major clinical problem.”
Teitelbaum and colleagues including lead author Hyun-Ju Kim, Ph.D., a postdoctoral fellow, publish their results in the August issue of the Journal of Clinical Investigation…
Earlier attempts to identify the connection between bone loss and cortisone produced seemingly contradictory results. In lab animal experiments, researchers found cortisone caused bone-building osteoblast cells to self-destruct, suggesting that cortisone disrupts the body’s ability to form new bone after it is naturally dismantled by osteoclasts. However, experiments in the test tube also showed cortisone stimulates bone formation.
Teitelbaum identified a new opportunity for exploring the conundrum while at a lecture by Washington University colleague Louis J. Muglia, M.D., Ph.D., director of pediatric endocrinology at St. Louis Children’s Hospital. Muglia’s group studies the health effects of stress, many of which are mediated by cortisone. To aid his research, Muglia developed a line of genetically modified mice where receptors for cortisone, which are found throughout the body, could be selectively eliminated in individual cell types.
By crossbreeding their genetically modified mouse lines, researchers produced a line of mice whose bone-dismantling osteoclasts lacked cortisone receptors. When researchers gave cortisone to these mice, the bone-weakening effects of the drugs were blocked.
In addition, scientists found that cortisone inhibits the ability of osteoclasts to dismantle old bone in genetically normal mice. This blockage might seem to leave bones free to retain their strength, but with the regular skeletal renewal process stopped, bones will weaken dramatically from aging and stress. Dampening of osteoclast activity may also cause a chain reaction that slows activity of bone-building osteoblasts.
“We now have an idea of what’s happening from a viewpoint of 1,000 feet up or so,” says Teitelbaum, comparing the new insight to sighting a highway from an airplane window. “Now we’ll start looking more closely at the molecular mechanisms involved to see if we can generate therapeutic targets.”
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