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Signaling protein builds bigger, better bones in mice

ANN ARBOR, Mich. Leaping tall buildings in a single bound may be out of the question, but the genetically engineered "supermice" in Ormond MacDougald's laboratory at the University of Michigan Medical School are definitely stronger than average. With bone mass up to four times greater than ordinary mice, these research animals could hold the secret to new drugs for preventing or treating osteoporosis and other human diseases.

The secret appears to be a secreted signaling protein called Wnt10b. Known to inhibit the development of adipose tissue in mice, Wnt10b also stimulates the growth of bone cells, according to a new study that will be published February 21 in the Online Early Edition of the Proceedings of the National Academy of Sciences.

"High levels of Wnt10b expression in bone marrow directly increased bone mass and density in our experimental mice," says Ormond A. MacDougald, Ph.D., associate professor of molecular and integrative physiology in the U-M Medical School. "This is the first identification of a specific signaling protein in the Wnt family that regulates bone formation."

Wnt10b is one of a family of 19 related proteins. Wnts (pronounced "wints") regulate the complex changes that take place as an embryo develops. One step in this process determines the fate of primitive cells called mesenchymal stem cells.

"In bone marrow, mesenchymal stem cells have the potential to become either fat cells called adipocytes or bone-forming cells called osteoblasts," MacDougald says. "In adult animals, including humans, there's a reciprocal relationship between bone and marrow fat. Our research indicates that Wnt10b's signal blocks the fat cell pathway and stimulates the osteoblast pathway, which means less fat and more bone."

To study the effect of Wnt10b gene expression on tissue development, MacDougald's research team created an artificial sequence of DNA called a transgene linking Wnt10b to the FABP4 promoter, whi
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