Best Osteoporosis Defense May Be a Good Offense

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Best Osteoporosis Defense May Be a Good Offense

Wed May 15, 5:11 PM ET

By Ed Edelson

HealthScoutNews Reporter

WEDNESDAY, May 15 (HealthScoutNews) -- 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 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 (news - web sites).

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