News Release

Cellular espionage at play in post-menopausal osteoporosis

Peer-Reviewed Publication

Washington University in St. Louis

Bone researchers have long known that post-menopausal women are at increased risk of bone loss and diseases such as osteoporosis because of low levels of the hormone estrogen. In recent years, estrogen replacement therapy has been the course of action to prevent bone loss in such women. But not all women are acceptable candidates for this therapy because some may be predisposed to breast, uterine and ovarian cancer risks if they take increased estrogen.

Despite advances in estrogen replacement therapy, it is a source of hot debate in the biomedical community over what cell, molecular and biochemical processes are involved in bone loss associated with declining estrogen levels.

Now a group of biologists at Washington University in St. Louis has shown that lower estrogen levels in post-menopausal women allow a class of inflammatory molecules called cytokines to bind to bone cell surfaces. This in turn gives the green light for specialized cells called osteoclasts to perform their specialty -- bone resorption, or destruction. Moreover, the Washington University team headed by Philip Osdoby, Ph.D., professor of biology in Arts and Sciences, and Teresa Sunyer, Ph.D., research assistant professor of biology, has shown a new relationship between estrogen, bone cell surface receptor proteins and the cytokines Interleukin 1 (IL-1) and Interleukin 8 (IL-8).

Their findings reveal a "cellular espionage" scenario involving signaling receptor proteins and decoy receptor proteins. Osdoby, Sunyer and colleagues found that, in the presence of estrogen, decoy receptor proteins increase in bone cells, preventing cytokines from initiating the path of bone destruction. Without estrogen, signaling receptor proteins flourish and the decoys diminish, letting the osteoclasts erode bone.

The results were published in the May 15, 1999, issue of the Journal of Clinical Investigation. The research was supported by grants from the National Institutes of Health.

Besides providing a better understanding of the cellular processes leading to post-menopausal osteoporosis, the findings have implications for several other bone disorders ? osteoporosis, rheumatoid arthritis, periodontal disease, osteoarthritis and the bone destruction that can occur with artificial joint implants. It gives the pharmaceutical industry additional clues to develop compounds that can specifically prevent cytokine formation in bone cells, and thus stop bone loss from occurring.

"This is another piece of the complex puzzle of pathological bone-loss problems," says Osdoby. "These receptor proteins may have the potential to serve as targets for therapeutic strategies, especially in estrogen replacement therapy. We and others think that one key to the complex interplay of events leading to bone destruction is preventing IL-1 from getting started in the bone cells."

Osteoclasts are large, multinucleated cells that thrive in the bone environment. They work in a strangely complementary manner with bone-forming cells called osteoblasts in the bone remodeling process. This is a lot like the erosion/deposition process of a riverbank where material is removed and then deposited once again. The osteoblasts give; osteoclasts take away. In balance, the two cell types actually promote healthy bone by maintaining a sort of equilibrium.

Osdoby, Sunyer and their Washington University collaborators -- Jennifer Lewis, a medical student and former Howard Hughes undergraduate fellow, and Osdoby's wife, Patricia Collin-Osdoby, Ph.D., research associate professor in biology -- performed a variety of assays to reach their conclusions. They took bone cells donated from post-menopausal accident victims and from hip-fracture patients provided by researchers at the Washington University School of Medicine and used micromolecular techniques to determine relative levels of IL-1 signaling and decoy receptors present on these cells.

Answering biological questions
"When we first started doing this, we noticed great variability in the ratio between signaling receptors and decoy receptors, and we wondered if that was a function of age or estrogen status," says Osdoby. "We clearly saw that as a function of age in women there is an increase in signaling receptors and a decrease in the decoy receptors.

"Seeing this, we had to ask: can we translate this into a biological process associated with diminished estrogen? So we set up experiments to ask the question: If we add estrogen to the cells, can we alter the ratio of the signaling and decoy receptors? We saw an increase in decoy receptors and a decrease in signaling receptors upon adding estrogen to osteoclasts, but not when we performed the same experiments in bone-forming osteoblasts. This suggested that the estrogen effect was selective for the bone-degrading osteoclasts. To determine if the estrogen-mediated changes in IL-1 receptors translated into osteoclast responses to this cytokine, we pretreated the cells with estrogen and then treated them with IL-1 to determine if the IL-1 response is suppressed."

Osdoby looked at two things: the production of IL-8, made by osteoclasts and stimulated by IL-1, and its effect with added estrogen; and the survival of osteoclasts in the presence of estrogen. He found that estrogen prevented the IL-1/IL-8 destructive connection and it diminished IL-1 mediated osteoclast survivability.

Osdoby and his group have concentrated on osteoclast behavior and activity in a series of published papers over the past 19 years. The original work on the osteoclast cell surface proteins in 1984 sought to determine the nature of receptor proteins on the osteoclast and it has led to a number of basic biological questions with clinical implications.

For instance, how did the two IL-1 receptors and their regulation of expression develop? "No one really knows how the decoys evolved," says Osdoby. "But it's a remarkable kind of competition, and adding this small revelation regarding estrogen regulation is a potential boost to pharmaceutical possibilities. There are a number of exciting therapies in the works and this kind of information about the receptors might help evolve more specific therapies."

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