NEWS CONFERENCEFriday, March 9, 20011:30 p.m. CTZ On campus - UAMS Chancellor's Areain the Board Room (Room M1/131)
WEB RESOURCES
Stavros Manolagas, M.D., Ph.D.Phone: 501-686-5130E-mail: [email protected]
Scientists at UAMS Activate Bone Cell Rescue Pathway
(Little Rock, AR) Twenty-eight million Americans have reason for new hope in dealing with osteoporosis - a devastating bone-wasting process that puts half of older women and one in eight men over 50 at greater risk of hip and other debilitating bone fractures.
By manipulating how sex steroids are processed in bone-building cells called osteoblasts, a research team at the University of Arkansas for Medical Sciences (UAMS) in Little Rock, Arkansas, led by Stavros C. Manolagas, M.D., Ph.D., has shown it may be possible to increase the survival of these cells. "This research points the way to avoiding many of the complications associated with current estrogen hormone replacement therapy," Dr. Manolagas said.
The finding, published in the March 9, 2001 issue of the scientific journal, Cell, could have important implications for the development of new drugs to prevent or treat osteoporosis in both women and men.
In cell culture experiments, the UAMS research team successfully used synthetic molecules that mimic some good yet avoid the bad effects of estrogen, a sex hormone present in women and men. They selectively activated the anti-apoptosis, or "cell rescue" pathway of estrogen and androgen receptors in mouse bone cells. By activating only this pathway, the scientists were able to promote the longevity of osteoblasts, the cells that lay down new bone, without sparking detrimental sex steroid activities within the cell. Preserving osteoblasts could help prevent osteoporosis, a bone-wasting disease, which is a major health risk to persons over age 50.
"Our work, for the first time, delineates the way sex steroids might protect bone-forming and bone-maintaining cells from cell death in both women and men. This presents an opportunity for unisex application of our work," Manolagas said. He believes the research is the foundation for developing new and improved treatments for osteoporosis based on only the "good" properties of estrogen.
Manolagas is the Director of the Division of Endocrinology and Metabolic Bone Diseases and a Professor of Medicine at the UAMS College of Medicine. He serves as a faculty physician and researcher at UAMS Medical Center and the Central Arkansas Veterans Healthcare System.
Jill Carrrington, Ph.D., director of the musculoskeletal biology program at National Institute on Aging, commented, "With further work to understand this mechanism, it may be possible to design new treatments for osteoporosis." The National Institute on Aging (NIA) and the National Institute on Arthritis and Musculoskeletal and Skin Diseases (NIAMS), two components of the National Institutes of Health (NIH) in Bethesda, Maryland, supported the research.
The research team includes: S. Kousteni, T. Bellido, D.L. Bodenner, K. Han., J.A. Katzenellenbogen, B.S., Katzenllenbogen, P.K. Roberson, R.S. Weinstein, R.L. Jilka, and S.C. Manolagas. The article is entitled, "Non-Genotropic, Sex Non-Specific Signaling Through The Classical Estrogen or Androgen Receptors: Dissociation From Transcriptional Activity."
In the United States today, 10 million individuals already have osteoporosis and 18 million more have low bone mass, placing them at increased risk for this disease. Osteoporosis is responsible for more than 1.5 million fractures annually, including 300,000 hip fractures, approximately 700,000 vertebral (spinal) fractures, 250,000 wrist fractures, and more than 300,000 fractures at other sites. In addition to hormone replacement therapy, exercise and adequate intake of calcium and vitamin D can help preserve bone mass and prevent or slow osteoporosis in older women and men.
The National Institute on Aging is a component of the National Institutes of Health, U.S. Department of Health and Human Services. The NIA and the NIAMS, are two of 26 institutes and centers that compose the NIH. The NIA leads the federal effort supporting and conducting research on aging and age-related diseases and special needs of older people. NIAMS leads the Federal effort on research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases.
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New Research Finding on Estrogens and Androgensby Stavros C. Manolagas, M.D., Ph.D.
Estrogens and Androgens, the female and male sex hormones, are steroids - small chemicals that modify the function of many cells and tissues around the body. After these chemicals are released into the circulation from the site of their production, primarily the gonads, they are targeted to cells that contain intracellular proteins that are localized on the cell nucleus and recognize the steroids like locks recognize a key. Upon binding of the small steroid molecules to the receptor proteins, the latter change their three-dimensional shape in such a way so that they can form complexes with other proteins. These complexes then are able to recognize specific genes and turn them on or off, over a period between one half and three to four hours. These actions are responsible for the dimorphism of the genders and their respective function in reproduction.
In the studies reported in the March 9th issue of Cell, investigators from the University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System have found that a fraction of the classical receptors for estrogens or androgens, or a small part of these proteins, must be localized in the inner side of the outer cell membrane. Upon recognition of the steroids, these membrane-associated receptors are turned on in such a way as to trigger a fast signal (within minutes) that travels from the membrane to the interior organelles of the cells and prolongs the survival of many cell types. Among such cells are the cells responsible for the formation and maintenance of bone. This fast signal is transmitted through a portion of the receptor protein that is different from that which is responsible for turning genes on and off in the nucleus.
Very surprisingly, unlike the effects of sex steroids on the activity of genes that are gender specific, the survival promoting fast actions discovered in these studies are sex non-specific; in other words, the estrogen receptor can transduce the signal of androgens and the androgen receptor the signal of estrogens. More important, the workers have shown that one can dial out the fast from the long-term actions of the receptors with certain synthetic compounds.
"I believe that these discoveries represent an important conceptual breakthrough, as they open avenues for the development of a new generation of drugs, for diseases like osteoporosis, or new forms of hormone replacement therapy" said Stavros Manolagas, M.D., Ph.D., Professor of Medicine and the senior author of the paper. Because such drugs may split one activity of the receptor from the other they may be able to build and restore bone mass - contrasted with existing drugs that can only prevent or retard bone loss. In addition, because they can work through the estrogen or the androgen receptor they have the potential of being gender neutral, meaning they could be used for both males and females. Because they lack the long-term effects on genes controlling reproductive function they are also expected to avoid the undesirable effects of the ordinary forms of estrogen replacement on the uterus (such as uterine cancer and continuous menstruation) and breast (such as mastodynia and breast cancer). Finally, because some of the beneficial actions of estrogen on the blood vessel and brain cells are mediated through fast signals, similar to those found in these studies, these new drugs may also have protective effects on brain and cardiovascular function.
Bone RegenerationHealthy bone is continually removed and rebuilt by a process referred to as remodeling. Cells that remove old bone are called osteoclasts and cells that replace and repair the tissue are called osteoblasts. Osteoclasts stick to the bone and destroy minute sections by releasing acid, then ingesting the remnants. Osteoblasts then move in to cover the excavated area and start the process of building new bone. Bone mass is maintained at a constant level due to the tight balance of bone removal and rebuilding. Both osteoblasts and osteoclasts are created from precursors in the bone marrow, and after performing their respective functions, they are programmed to die by a process called apoptosis.
OsteoporosisOsteoporosis (loss of bone mass) is a disease affecting over 25 million people in the United States, and over 200 million people worldwide. This disease will affect approximately 80% of women during their lifetime. Over $10 billion is spent in health care each year for treatment of this disease, and this amount is projected to increase to over $60 billion in the next 30 years.
Osteoporosis can lead to fractures after little or no trauma. Common sites for fractures are the wrist, rib, vertebra, and the hip. Such fractures may occur in women and men of any age and may leave a patient confined to a wheel chair. Moreover, up to 20% of patients die after a hip fracture and 40% can no longer live independently. The main risk factors for the development of this disease are sex hormone deficiency in females or males, old age, and the use of anti-inflammatory steroids.
Estrogen DeficiencyThe form of osteoporosis that is most prevalent in women is caused by a deficiency in the female hormone, estrogen, occurring around the time of menopause. Estrogen keeps the rate of bone remodeling low and shortens the working life of osteoclasts while it increases the working life of osteoblasts. Thus, the balance is maintained between bone removal and building. When women reach menopause, estrogen deficiency results in accelerated bone remodeling. Moreover, a decrease in the life span of osteoblasts combined with an increase in the life span of osteoclasts leads to an imbalance between building and removal that results in the progressive loss of bone. A similar mechanism seems to operate in the case of androgen deficiency, which happens in many elderly males, albeit later in life than the menopause in women.
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Brief bio of Stavros C. Manolagas, M.D., Ph.D.
Stavros C. Manolagas, M.D., Ph.D., is the Director of the Division of Endocrinology and Metabolism, the Director of the Center for Osteoporosis and Metabolic Bone Diseases, and a Professor of Medicine at the UAMS College of Medicine in Little Rock, Arkansas. He serves as a faculty physician and researcher at UAMS Medical Center and the Central Arkansas Veterans Healthcare System.
Dr. Manolagas received his doctorate of medicine from the University of Athens Medical School in Athens, Greece. He served his residency at Stepping Hill Hospital in Stockport, England, and was a fellow in endocrinology at Manchester Royal Infirmary, University of Manchester, England. Prior to his present position, he was on the faculty of the University of California at San Diego for nine years, and Indiana University for six years.
Author of over 200 articles, book chapters, and abstracts, Dr. Manolagas' research activities include the pathophysiology of Osteoporosis and other disorders of bone and mineral metabolism, and the interactions of the endocrine and the immune system.
He is a member of the highly prestigious Association of American Physicians (Old Turks), the American Society for Bone and Mineral Research, and the American Association for the Advancement of Science.
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