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Best Osteoporosis Defense May Be a Good Offense

Gene mutation discovery points way to bone buildup

WEDNESDAY, May 15, 2002 (HealthDayNews) -- A genetic discovery has opened the way to a revolutionary way of treating osteoporosis, the bone-weakening condition that affects millions of older Americans.

Studies have identified a gene that is intimately involved in the buildup and breakdown of bones. Now, a group led by Drs. Karl Insogna and Richard P. Lifton at Yale University says it has identified a protein-gene interaction that is "a potential target for the prevention or treatment of osteoporosis."

All existing treatments for osteoporosis aim to reduce bone loss. The new genetic finding may make it possible to develop therapy that actually increases bone buildup.

The story began just last year, when researchers at Case Western University reported that if a mutation knocks out function of the gene, which is designated LRP5, people who carry the mutated gene develop severe bone loss at an early age, says Lifton, a professor of genetics and medicine at Yale.

"This raised the question in our minds whether a different mutation in the same gene could cause unusually high bone density," Lifton says. "We identified a family in which a mutation in a single gene causes them to have massive bone density. So there are two mutations, one that knocks out the gene and causes lower bone density, the other that increases gene activity and raises bone density."

A key to the way the gene controls bone density is a protein designated Dkk-1, Lifton says. When Dkk-1 locks onto the LRP5 gene, the result is decreased activity of the gene.

"This suggests for the first time that if we inhibit the ability of Dkk-1 to reduce LRP5 activity, we can raise bone density in normal individuals," Lifton says. "We would predict that this would not have other adverse consequences, because the people who have such a mutation do not have other abnormalities."

The most notable abnormality other than increased bone density associated with the LRP5 mutation is torus palatinus, a bony growth of the hard palate that occurs in 20 percent to 25 percent of the general population.

One obvious strategy is to find a molecule that locks onto the Dkk-1 protein and prevents it from functioning.

"But I would be reserved about interfering with Dkk-1 because it might be doing a number of other things," Lifton says. "If we target LRP5 instead, that would do the trick."

A number of research groups, including some in the pharmaceutical industry, are looking for such compounds, Lifton says.

One researcher working in that area is Dr. Gerard Karsenty, a professor of genetics and medicine at Baylor College of Medicine and co-author of an editorial accompanying the report in tomorrow's issue of the New England Journal of Medicine.

Rather than looking directly at the Dkk-l/LRP5 interaction, Karsenty is studying the chain of molecular events that is triggered by that interaction.

"We are looking for interactions within the cell, from the gene downstream," he says.

One great surprise is that LRP5 has such an important role in bone regulation, Karsenty says. "It is expressed almost everywhere all the time, and is not controlled by any of the hormones we know about," he says.

What To Do: You can learn what we know about osteoporosis and its treatment from the National Library of Medicine or the National Osteoporosis Foundation.

SOURCES: Richard P. Lifton, M.D., professor, genetics and medicine, Yale University School of Medicine, New Haven, Conn.; Gerard Karsenty, M.D., Ph.D., professor, genetics and medicine, Baylor College of Medicine, Houston; May 16, 2002, New England Journal of Medicine
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