Scientists are closing in on the solution to a persistent medical puzzle: why do high doses of cortisone, widely prescribed for asthma, rheumatoid arthritis and other inflammatory and autoimmune conditions, weaken bones?
Among other findings, researchers showed that cortisone inhibits resorption of bone, a dismantling process necessary to renew bone and maintain its strength. In the images above, dark areas (marked with arrows) show bone being resorbed. Bone in the image on the left had not been exposed to cortisone and is being resorbed at multiple sites; on the right, a full dose of cortisone has dramatically inhibited those processes.
Through studies of mice, researchers at Washington University School of Medicine in St. Louis have now identified osteoclasts, cells that dismantle old bone, as the essential link between osteoporosis and cortisone. As scientists flesh out the molecular-level details of this connection, they may be able to identify targets for therapy to prevent cortisone's damaging side effects on bone.
"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.
Cortisone is a steroid produced naturally by the adrenal gland and synthesized by a number of pharmaceutical companies for clinical use. The drug is also used to treat lupus, multiple sclerosis and chronic obstructive pulmonary disease, and it is prescribed to transplant patients to prevent rejection of transplanted organs.
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."
Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, Ross FP, Teitelbuam SL. Glucocorticoids suppress bone formation via the osteoclast. The Journal of Clinical Investigation, August 2006.
Funding from the National Institutes of Health supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.