UF scientists discover novel mechanism underlying bone destruction

November 14, 2000

GAINESVILLE, Fla. --- University of Florida researchers have discovered a new way bone-destroying cells function in the body that could pave the way for the development of new drugs to treat osteoporosis as well as some of the most deadly forms of cancer.

The scientists have uncovered a crucial interaction between an enzyme and osteoclasts, cells in the body that remove bone in a natural cycle of bone growth and breakdown. The connection between the enzyme, vacuolar proton adenosine triphophatase or V-ATPase, and the osteoclasts may provide a novel target for future medications to block the bone erosion associated with osteoporosis and the deadly metastatic bone diseases that stem from breast and prostate cancers.

"This is an important step in bone disease research because it opens up the possibility that there may be an entirely new way to treat disorders like osteoporosis, arthritis and bone-deforming Paget's disease, as well as cancers that infiltrate bone," said L. Shannon Holliday, who will present the research at the American Society for Cell Biology's annual meeting in December.

"Finding new ways to treat these diseases is critical because as the U.S. population grows older over the next 25 years, bone disease will play an increasingly prominent role not only in how long people live, but particularly in how good their quality of life is when they get to old age," said Holliday, a research assistant professor in the UF College of Medicine's departments of medicine, and anatomy and cell biology. It could take five years or more to develop pharmaceuticals targeting the enzyme-osteoclast connection, he said.

Osteoporosis is linked to more than 1.5 million fractures a year in the United States and an estimated $13.8 billion in direct care costs to hospitals and nursing homes, according to the National Institutes of Health. More than 10 million people, mainly women, suffer from the disease, and that number is expected to grow. Another 18 million Americans have low bone mass, placing them at increased risk for the disease.

Osteoclasts play an important role in the body in the routine process of bone removal and growth. But in bone diseases including osteoporosis, the osteoclasts are overly active and out of balance with their bone-building counterparts, osteoblasts. As a result, bones begin to deteriorate.

That deterioration also causes bones to become vulnerable to invasion by metastasizing breast and prostate cancer cells. Once they invade bones, these cancer cells can't be treated effectively by conventional cancer therapies. When osteoclasts encounter bone, they attach themselves to it, forming a connection similar to a suction cup. Using tissues from mice and cows, UF researchers discovered that when the link takes place, microfilaments help move the enzyme V-ATPase from the core of the osteoclast to its surface. Once there, the enzyme pumps acidifying elements called protons that cause the bone to degrade.

"The finding suggests that bone destruction could be halted if the enzyme transfer could be interfered with," said Holliday, whose article describing the research was published last month in the Journal of Biological Chemistry. Holliday also presented the findings at recent annual meetings of the American Society for Bone and Mineral Research and the American Society of Nephrology.

The research was conducted in collaboration with Dr. Stephen Gluck, a leader in V-ATPase investigation for many years. Gluck is a professor and chief of UF's division of nephrology, hypertension and transplantation. UF scientists will continue their research to find ways to prevent the enzyme shift. Currently, there are drugs available to treat bone diseases, but none are optimal.

"All of them have side effects or down sides, or they aren't as effective as they could be," Holliday said.

Biphosphonates are the most common medications prescribed to treat osteoporosis and Paget's disease, in which the excessive breakdown and formation of bones causes them to become enlarged, deformed and weakened.

These medications can be difficult to take because they must be taken on an empty stomach; furthermore, for 30 minutes afterward lying down and eating or drinking anything but tap water are prohibited. There also are questions about whether the medications will cause any harmful long-term effects on bones, he said.

In addition, the mechanisms by which some of the most common bone disease drugs function are not well understood. Biphosphonates, for example, inhibit osteoclasts, but it is unclear how they do so, Holliday said.

"They've become very important pharmaceuticals for treating bone disease," Holliday said. "But we're still searching for the magic bullet. With the knowledge gained by our recent discovery, in principle at least, we can develop new drugs that are more efficacious than what's currently available." Holliday collaborated with other UF researchers and scientists from the Washington University School of Medicine in St. Louis and the University of Utah in Salt Lake City. The research is part of a three-year study funded primarily by the Arthritis Foundation in association with the National Institutes of Health.

"These studies represent a significant advancement to our understanding of the complex question of how osteoclasts are able to initiate bone resorption at the proper place and time, a necessary function for normal bone health," said Fred Pavalko, an associate professor of cellular and integrative physiology at Indiana State University School of Medicine. "It is possible that information like this will help us better understand the pathophysiology of bone diseases such as osteoporosis that affect so many people."

University of Florida

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