Of Mice And Bones

February 16, 2007
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GRAND RAPIDS — Scientists at the Van Andel Research Institute have developed a method to increase bone density in mice by “turning off” the gene known as PTEN in the cells that build bone.

VARI researchers conducted the study in collaboration with researchers from the Center for Metabolic Bone Disease at the University of Alabama at Birmingham. The results were published in last Tuesday’s issue of the Proceedings of the National Academy of Sciences journal.

VARI Senior Investigator Bart Williams, Ph.D., explained that bone density can increase either because more bone cells divide or fewer bone cells die. The researchers found a way to disrupt the PTEN gene in osteoblast bone cells, which are specialized bone cells that generate new bone material. All 20 mice in the experimental group developed dramatically increased bone mass compared to the control group, Williams said.

The PTEN gene regulates the cycle of cell division by keeping cells from growing and dividing too fast or in an uncontrolled manner. The PTEN enzyme acts as part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct when necessary. Those functions prevent uncontrolled cell growth that can lead to the formation of tumors.

While osteoblasts build bone, their activity is balanced by osteoclast bone cells that break down bone material. In the bones of healthy adults, for instance, bone mass remains relatively stable because osteoblasts and osteoclasts work at about the same rate. Part of the reason humans lose bone density as they age is because osteoblast cells die off, and that can lead to osteopenia or osteoporosis, according to scientists.

The researchers did a longitudinal analysis of the whole-body bone mineral density of 40 mice over a two-year period. For the experimental group, the scientists created 20 genetically altered mice with a deactivated PTEN gene in their osteoblast cells. With the disruption of the PTEN gene, the osteoblast cells survived longer and continued to make new bone long after they ordinarily would have died, Williams said. Compared to the control group, both male and female mice displayed significant increases in bone mineral density as they aged; by 15 months of age, female mice had 71 percent higher whole-body bone mineral density and males had 60 percent higher bone mineral density than the control group.

Williams said the next step will be to look at other genes that might interact with the PTEN gene and see if they cause similar or different effects. His team has had discussions with some of the orthopedic surgeons in the residency programs at Spectrum Health and Saint Mary’s about coming over to the institute and looking at the study in more detail to see how it may be applicable to humans.

“In this animal we have proven the concept that altering this gene can increase the amount of bone,” Williams said. “What we have to do now is to decide how we can mimic this effect in humans; it might be by gene therapy or a pharmaceutical agent but that’s probably quite a ways away. With any discovery made in a basic research laboratory, you’re looking probably at a minimum five or six years before you can even go into that step, and four or five years to establish that it works in humans.”

Current treatments for osteoporosis block the breakdown of bone, which helps slow bone loss but doesn’t help build new bone or help increase bone density after it has been lost, Williams said.

The goal now is to find a way to selectively turn off PTEN only in bone-making osteoblasts without affecting other cells, Williams said. Hopefully, he added, VARI researchers and others can pursue ways to specifically inactivate PTEN in osteoblasts in order to build bone to treat osteoporosis in the long term, or maybe to treat fractures by increasing the rate of healing.

Williams said the study could have implications for cancers that, in advanced stages, start growing in the bone.

“There’s a lot of interest in trying to understand how cancer cells interact with the bone cells, so there are always at least some indirect implications for understanding how the process of skeletal metastasis from prostate cancer, for instance, works,” he said. “There are developmental abnormalities in children that occur in terms of bone growth, so the study could probably have unanticipated implications for many things.”

Williams recently presented results of the study at scientific meetings in Colorado and Pennsylvania, and his collaborator at the University of Alabama has presented the results at a meeting in Massachusetts.

“We’ve received positive responses and interest in how to extend this observation to other studies,” he added. “That’s really how science works; you publish your observation and people throughout the world will read it, and maybe it will give them some ideas of how to extend their own work.”

The research was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, one of the National Institutes of Health, and by the Van Andel Institute. The researchers are seeking another NIH grant to continue their study and expect to hear from NIH within the next couple of weeks.

Williams said the goal is to use the resources the Van Andel Institute has to generate publications and data that can be used to secure federal funding and increase the number of researchers working in Grand Rapids.

“One of the advantages of working at the Van Andel Institute is that you can begin studies like this without having to get the initial seed money to do it, which is always the most challenging thing,” he explained. “Once you’ve generated data and publications, it’s a lot easier to go to outside funding sources, including federal sources, for grants because they can see that you’ve been able to accomplish things.”    

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