Teitelbaum:
Led osteoporosis studyBy Gila Z. Reckess
May 4, 2001
Researchers have the first evidence that a protein essential to both bone-degrading cells and to platelets that help blood clot plays two distinct roles.
"By taking advantage of this finding, we might be able to develop drugs that selectively influence one system or the other," said Deborah V. Novack, M.D., Ph.D. "Then we'll have a much more specific therapy to treat bone diseases without harming platelets, and vice versa."
| Teitelbaum:
Led osteoporosis study |
Novack, instructor in pathology, is first author of a paper in the May 1 issue of the Journal of Clinical Investigation. Xu Feng, Ph.D., research associate in pathology, is the other first author. Steven L. Teitelbaum, M.D., the Wilma and Roswell Messing Professor of Pathology, led the study.
The protein, beta-3 integrin, sits on the cell surface, fielding messages from its surroundings. It is found on cells called osteoclasts, which break down bone and therefore can contribute to osteoporosis. And it also sits on platelets. Defects in beta-3 integrin cause a rare bleeding disease called Glanzmann's thrombasthenia.
"So if you treated osteoporosis with a drug that blocks the entire beta-3 integrin molecule, patients would have problems with bleeding because of platelet dysfunction," Novack said.
She and her colleagues created the first strain of mice that completely lacks beta-3 integrin. The animals' osteoclasts were unable to function properly.
The researchers cultured these osteoclasts in a dish and added back the gene for normal beta-3 integrin. This manipulation enabled the cells to function normally. But a gene with a piece missing was unable to restore normal function. The missing piece coded for the tail of the beta-3 integrin molecule. The tail pokes into the cell, conveying messages from the exterior.
This experiment showed that the tail is needed for normal osteoclast function. To find out which parts of the tail are essential, the researchers inserted six altered beta-3 integrin genes into different osteoclast cells. Each gene had either one or two mutations in the DNA that codes for the tail.
Five of the six variant genes enabled the osteoclasts to break down bone, showing that the parts of the molecule containing those mutations are unimportant for osteoclast function. One of the five, a double mutation, was previously shown to disrupt platelet function.
The sixth mutation failed to restore the osteoclasts' ability to break down bone. Osteoclasts with this mutation acted the same as cells without any form of beta-3 integrin. Therefore, that part of the molecule is essential to osteoclast function. It also appears to be essential to platelet function because mutations in this part of the gene for beta-3 integrin cause Glanzmann's thrombasthenia.
"We have shown that there are both similarities and differences in the function of beta-3 integrin in platelets and osteoclasts," Novack said. "Finding a mutation that affects osteoclasts but not platelets might point the way to a new treatment for osteoporosis."
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