In a report that appears online today in the journal Nature, Dr. Gerard Karsenty, BCM professor of molecular and human genetics, and his colleagues demonstrate in mice that the sympathetic nervous system mediates the resorption or destruction of bone through a special receptor on bone cells, and that this effect is required for the development of osteoporosis after menopause in mice. Preventing the sympathetic nervous systems from activating this receptor could prevent osteoporosis.
An estimated 10 million Americans over the age of 50 and 30 million people worldwide have osteoporosis, a disease in which there is less bone mass and a high risk of fracture. Each year, 1.5 million Americans suffer a fracture because of the disease. In a report last October, the U.S. Surgeon General estimated that the cost of caring for people with osteoporosis-related fractures totals $18 billion per year, a figure that will increase unless prevention efforts improve.
Karsenty's work started five years ago when his group demonstrated that one of the main functions of leptin, a hormone initially thought only to regulate appetite, is to regulate bone formation. Later, they showed that the sympathetic nervous system mediates only this action of leptin.
In the most recent study, they showed that leptin also affects bone destruction or resorption through a receptor for the sympathetic nervous system present on bone cells.
Mice lacking this receptor have "what every woman at time of menopause would like to experience," said Karsenty. "They make more bone, they destroy less bone and do not lose bone when their ovaries are removed. This is the first demonstration that nerve cells are involved in osteoporosis development. This has tremendous clinical implications especially since these mice are not obese."
Drugs that inhibit the sympathetic nervous system are already commonly in use. They are called beta blockers and a study in the Journal of the American Medical Association (JAMA. 2004 Sep 15;292(11):1326-32) buttresses Karsenty's hypothesis, by demonstrating that older patients with osteoporosis who took beta blockers had fewer fractures than those who did not.
"The task now is to develop beta blockers that are specific to bone and do not affect cells in the heart muscle. Then you would have the prevention of osteoporosis with a safe drug and no heart effect. There is a lot of reason to believe it can be done," said Karsenty.
He is also studying the effect of beta blockers on men who have undergone surgical castration as treatment for prostate cancer. This study is being carried out in collaboration with The University of Texas M.D. Anderson Cancer Center in Houston.
Others who participated in the research include: Drs. Florent Elefteriou, Jong Deok Ahn, Shu Takeda, Michael Starbuck, Xiangli Yang, and Xiuyun Liu, all of BCM; Hisataka Kondo and Masaki Noda of Tokyo Medical and Dental University in Japan; William G. Richards and Tony W. Bannon of Amgen Inc., in Thousand Oaks, California; Karine Clement of INSERM Avenir team; University Paris, and Christian Vaisse of the University of California, San Francisco.
This work was supported by grants from the National Institutes of Health, the National Space Biomedical Research Institute, the Children's Nutrition Research Center, the Arthritis Foundation and the Children's Brittle Bone Foundation.