Sci. Aging Knowl. Environ., 28 November 2001
Skeleton Crew: Disease gene points to new bone-building signal (Osteoporosis)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/9/nw33
Key Words: osteoporosis bone OPPG LRP5 Wnt OPS
Abstract: From a distance, a suspension bridge appears static. But the ride across reveals constant rebuilding: Workers sandblast and repaint rusted metal, replace decaying rivets, and recast worn roadways. Bones similarly undergo constant maintenance, and when the demolition team works faster than the construction crew, osteoporosis results. To fight this skeletal weakening, scientists have sought to understand how bone renovation is orchestrated. Now, researchers have pinpointed a gene that might play the role of molecular foreman in this process: A defective version of it appears to cause a rare childhood disease with symptoms similar to osteoporosis. The finding identifies a new pathway responsible for bone growth and might lead to the development of drugs that could shore up elderly skeletons.
Children with osteoporosis-pseudoglioma syndrome (OPS; also called OPPG), an inherited disorder, suffer from fractures and deformity as a result of abnormally low bone density. They don't appear to make enough bone, although the composition of the bone they do fabricate appears normal. To hunt down the gene responsible for OPS, Gong and colleagues searched a large region of chromosome 11 that they had previously shown contained DNA marker sequences commonly found in patients with the disease. In a small section of this large region, one OPS patient carried three of these genetic markers on both copies of chromosome 11. The researchers wondered whether that stretch harbored a gene that plays a key role in the disease. They zeroed in on a candidate called Lrp5 and sequenced it from members of 28 families afflicted by the disease. Within this group, the researchers found several mutations that probably disrupt the production of normal Lrp5 protein; DNA from normal subjects did not carry the mutations. These results strongly suggest that defective Lrp5 causes OPS, although definitive proof requires further evidence.
Previous work on several organisms indicates that Lrp5 and closely related genes encode proteins that coat the surface of cells and bind so-called Wnt proteins, secreted molecules best known for controlling body patterns--limb growth, for example--during embryonic development. To test whether the Wnt signal might also trigger bone growth, the team cultured so-called pluripotent mesenchymal cells, which can become bone cells or other cell types depending on extracellular molecular signals. They engineered the bone cell precursors--which naturally harbor the LRP5 protein--to produce and spew out a Wnt protein--Wnt3a--that the cells don't normally manufacture. Wnt3a production induced activation of genes that are turned on in bone cells if those cells also carry normal LRP5; in contrast, cells that produce a defective form of LRP5 that binds Wnt but can't transmit the signal into the cell didn't show the same bone-related molecular signs. The results suggest that the Wnt pathway, through the action of LRP5, instructs bone-building cells to get cranking and that defects in LRP5 short-circuit that signal and cause OPS.
Lrp5 mutations are rare enough that they probably don't contribute to most cases of osteoporosis in the elderly. But by understanding how the pathway directs bone growth, scientists hope to develop drugs that coax the skeletal construction team to work overtime and thereby to prevent osteoporosis in the elderly. An independent investigation also supports the approach: According to work announced in October at the annual meeting of the American Society for Bone and Mineral Research in Phoenix, Arizona, genetic changes in the same region of the chromosome can also lead to unusually high bone density. The area of the genome that contains Lrp5 might well help build a bridge to bone-bolstering treatments.
--R. John Davenport
Y. Gong et al. (The Osteoporosis-Pseudoglioma Syndrome Collaborative Group), LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513-523 (2001). [Abstract] [Full Text]
Citation: R. J. Davenport, Skeleton Crew: Disease gene points to new bone-building signal (Osteoporosis). Science's SAGE KE (28 November 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/9/nw33
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