Scientists Activate Bone Cell Rescue Pathway

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.