Gene influences density of the skeleton.

Lessons for normal human biology often come from studying the abnormal. Consider the discovery of the mutated gene responsible for osteoporosis pseudoglioma, a rare condition that leaves bones so brittle that affected individuals are usually wheelchair-bound by their teenage years.

Beyond accounting for the disease, the gene "gives us insight into how bone mass accrues during growth," says Matthew L. Warman of Case Western Reserve University in Cleveland.

The gene and its protein, known as low-density-lipoprotein-receptor-related protein 5 (LRP5), may also inspire new ways to treat more-typical osteoporosis and other common bone diseases, suggests Warman. He unveiled the genetic finding last week at the American Society of Human Genetics Meeting in San Diego. The international team that has pursued the disease gene will detail the discovery next month in CELL.

Adding to the story, a second research group has data suggesting that a variant of the gene may endow people with thicker-than-normal bones, and a third group confirms that mice unable to make LRP5 develop weak bones.

"This [protein] is certainly a regulator of bone-matrix density," concludes Daniel H. Cohn of Cedars-Sinai Medical Center in Los Angeles.

Warman, his colleague Yaoqin Gong, and their collaborators have searched for the osteoporosis pseudoglioma gene for almost a decade. Affected people have normal-looking osteoblasts--the cells that deposit bone's mineral matrix--but the cells don't do their job properly.

Osteoporosis pseudoglioma isn't just a bone disease, however. People with it are also born blind or lose their sight by the time they're teenagers.

It's not clear how both bones and eyes depend upon LRP5, which sits on the surface of osteoblasts and other cells. This protein can probably respond to multiple signals, says Warman. Identifying the molecules that bind to LRP5 is a high priority, he and Cohn agree.

A rodent study presented last month at a bone-research meeting in Phoenix supports the LRP5-osteoporosis pseudoglioma connection and hints at a therapy. Gerard Karsenty of the Baylor College of Medicine in Houston and his colleagues created mice with mutations in their LRP5 genes and found that the rodents developed osteoporosis and eye abnormalities.

The researchers also showed that treating mice with statins, cholesterol-lowering drugs that studies have suggested increase bone mass (SN: 1/15/00, p. 41), reversed the bone loss. It may be possible to develop a drug to activate LRP5 on osteoblasts, stimulating cells to strengthen bones and prevent or slow common osteoporosis, speculates Warman.

Work from researchers at Creighton University in Oklahoma and Genome Therapeutics in Waltham, Mass., supports the idea that the actions of LRP5 can increase bone mass. Those scientists have been studying a large family in which many members have thicker-than-normal bones. In family members with that trait, but not in other relatives, there is a subtle change in the LRP5 gene's DNA sequence, Randall D. Little of Genome Therapeutics and his colleagues reported at the meeting last week.