NEWS

St. Louis, April 18, 2000 -- Researchers have identified molecular interactions that must occur for certain cells to produce foot-like extensions called podosomes for movement. The findings could lead to osteoporosis and cancer drugs with fewer side effects.

"We've discovered the mechanism of podosome assembly, and the surprise is that it is unique compared with other forms of cell movement," says Keith A. Hruska, M.D., a kidney specialist at Washington University School of Medicine in St. Louis.

Hruska is the Ira M. Lang Professor of Nephrology and a professor of cell biology and physiology. He is senior author of a paper on podosomes in the April 21 issue of the Journal of Biological Chemistry that is posted at the journal's Web site. He had a related paper in the Feb. 21 issue of the Journal of Cell Biology.

Hruska studies how bone cells called osteoclasts function. The cells use podosomes to migrate to regions of bone that need degrading. Other bone cells rebuild these regions as part of the body's efforts to maintain a healthy skeleton. Overactive osteoclasts can cause osteoporosis, and Hruska has been identifying factors that regulate osteoclast function. Drugs that act on these factors might be able to combat the disease.

In the February Journal of Cell Biology, Meena Chellaiah, Ph.D, assistant professor of medicine, and Hruska reported that osteoclasts can't move or degrade much bone when they lack a protein that helps form podosomes. The osteoclasts were isolated from mice missing a protein called gelsolin, which interacts with molecules that give podosomes their shape and rigidity. This dramatic effect was unexpected because cells that move a lot, such as white blood cells and osteoclasts, have structural proteins that resemble gelsolin. "The osteoclast podosome is distinct in that it is completely dependent on gelsolin," Hruska says.

Mice lacking this key molecule developed thicker, stronger bones because of their osteoclasts decreased ability to degrade bone. The mice lived as long as normal mice and could readily produce offspring. However, they had minor abnormalities in the blood system, immune system and skin.

In the April Journal of Biological Chemistry, Hruska and Chellaiah identified factors that interact with gelsolin and therefore would make good targets for inhibitors of osteoclast movement. They studied

chicken osteoclasts that had been manipulated genetically to lack certain signaling factors or have overactive forms of these factors. These factors are thought to influence podosome development.

Hruska and Chellaiah found that chicken osteoclasts were unable to develop the foot-like extensions (podosomes) when they lacked a rare form of an enzyme called phosphatidylinositol-3'-kinase. This protein is present at sites where podosomes develop, and it produces a specialized fat molecule called phosphatidylinositol-trisphosphate. Hruska suggests that the specialized fat molecule serves as a glue, connecting proteins that form the internal structure of podosomes.

Another protein, Rho, is required to stimulate the enzyme phosphatidylinositol-3'-kinase. The researchers demonstrated that chemicals that inhibit gelsolin-associated proteins such as the enzyme and Rho caused osteoclasts to migrate less on whale bone and degrade less of the bone compared to normal osteoclasts.

The inhibitory chemical might become one of a family of drugs that shut down osteoclast activity and therefore slow the progression of osteoporosis. Because such a drug would target a rare enzyme, it likely would have few side effects. It also might work against cancer cells, which use podosomes to migrate to new sites in the body. As an added benefit, the drug would shore up the skeletons of people with cancer, whose bones tend to weaken as cancer invades them.

"Treating cancer patients with an inhibitor of podosome development such as this would help in two ways: by improving bone strength and shutting down metastasis," Hruska says.

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Chellaiah MA, Soga N, Swanson S, McAllister S, Alvarez U, Wang D, Dowdy SF, Hruska KA. Rho-A Is Critical for Osteoclast Podosome Organization, Motility and Bone Resorption. Journal of Biological Chemistry, 275 (16), pp. 11,993-12,002. April 21, 2000.

Chellaiah M, Kizer N, Silva M, Alvarez U, Kwiatkowski D, Hruska KA. Gelsolin Deficiency Blocks Podosome Assembly and Produces Increased Bone Mass and Strength. Journal of Cell Biology, 148 (4), pp. 665-678. Feb. 21, 2000.

The research was supported by a grant from the National Institutes of Health and by the Washington University/Monsanto Co. Biomedical Research Agreement.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.