A team of researchers from Emory University School of Medicine has found that bone loss and osteoporosis, a condition affecting more than 44 million men and women in the United States, may be caused by a 'thymic rebound' resulting from estrogen deficiency and the increased production of the protein IL-7.
The research is based on earlier findings suggesting a link between estrogen deficiency and an increase in the number and activity of T cells -- white blood cells that are an essential part of the body's immune system. After differentiating from stem cells in the bone marrow, T cells finish developing in the thymus. Increased T cell activity also leads to increased levels of the factor TNF, which also helps ward off infections but causes bone loss.
The Emory researchers have now discovered that a cause for the increase in T cells and TNF production is the reactivation of the thymus. These findings suggest the existence of a direct link between the functioning of the thymus and bone loss.
The findings appeared in the Nov. 2 online edition of the "Proceedings of the National Academy of Sciences." Roberto Pacifici, MD, Herndon professor of medicine at Emory University School of Medicine, is senior author, and Michaela Robbie Ryan, PhD, Emory postdoctoral fellow, is lead author.
According to Dr. Pacifici, scientists have long believed that the thymus is inactive after childhood, but he and his colleagues have discovered otherwise. "Our data shows that at least in the mouse -- and there is similar evidence in humans -- that with menopause and with lack of estrogen, the thymus surprisingly comes back to life and starts to pump out new T cells," Dr. Pacifici says, "This 'thymic rebound' results in a profusion of T cells, which, in turn, leads to increased generation of the factor TNF."
The scientists learned that the thymic rebound originates in a chain reaction set off by estrogen deficiency. This deficiency triggers increased production of the protein IL-7, which causes the production of new bone marrow stem cells and reactivates the thymus. This leads to increased output of TNF, the expansion of existing T cells, and the loss of bone mass.
By taking the thymus out of estrogen-deficient mice, the researchers determined that the organ is responsible for 50 percent of bone loss induced by estrogen deficiency. Dr. Pacifici explains, "Without the thymus the growth in the number of T cells induced by estrogen deficiency was 50 percent smaller, and loss of bone induced by estrogen deficiency was 50 percent less. So thymic rebound accounts for about half of the bone loss that takes place acutely when a mouse -- and we suppose a person -- becomes estrogen deficient."
The researchers also learned that blocking IL-7 stopped production of the T cells and TNF, and reduced bone loss.
The Emory researchers will continue to explore the implications of these latest findings by examining the relationship between the age of an estrogen-deficient subject and thymus activity.
Dr. Ryan says, "It would be fabulous to extend these studies into humans, to look at women who have undergone surgical menopause and see if in fact they do have thymic rebound, and tie it all together." If further research supports their recent findings, the researchers hope drugs might someday be available to stop IL-7 and reduce bone loss in humans.
Dr. Pacifici hopes that this new research will not only aid the battle against osteoporosis, but also serve as a reminder of the interconnectedness of the body. "This work reinforces the notion that the endocrine system and the hormones and the immune system work together," he says. "Hormones play a major role in regulating the immune functions, and if we want to understand how estrogen works and the mechanisms of menopause we need to look beyond just hormones and bone."
The research was supported by funding from the National Institutes of Health.