Scientists have discovered new information about an immune pathway in mice that explains how oxidative stress that results from acute estrogen deficiency leads to the loss of bone. The finding, published in the Proceedings of the National Academy of Sciences, could help in identifying a new drug target for preventing postmenopausal bone loss.
Previous mouse research has shown that both oxidative stress and increased T cell activity contribute to bone loss following estrogen depletion, which occurs after menopause or when ovaries are removed. Oxidative stress is the toxic accumulation of too much reactive oxygen in cells. Research has shown that T cells contribute to bone loss because they produce a protein called tumor necrosis factor (TNF), which increases the formation of osteoclasts in rodents and humans. Osteoclasts are cells that cause an excessive destruction of bone.
In the current study, scientists at Emory University School of Medicine, with colleagues at the University of Udine, Italy, discovered the "upstream" events that occur after estrogen depletion and lead to T cell overproduction. They found that reactive oxygen stimulates dendritic cells Ð a type of "antigen-presenting cell" that processes and presents antigen material on the surface of other immune cells Ð to up-regulate the immune antigen CD80. CD80 is a "co-stimulatory" molecule that is part of the CD80/CD28 pathway required for activation of T lymphocytes. When this pathway is activated, it leads to increased T cell TNF production and ultimately to bone loss.
In order to try and prevent bone loss in the research mice whose ovaries were removed and determine how reactive oxygen was exerting its toxic effects, the research team treated the mice with the immunosuppressant CTLA4-Ig, which prevents the activation of T cells by blocking the binding of CD80 to CD28. Because CTLA4-Ig did not directly affect osteoclasts or block the direct effects of reactive oxygen on osteoclasts, the data helped prove the researchers' hypothesis that oxidative stress causes bone loss because it activates T cells rather than acting directly on osteoclasts.
The research team was led by Roberto Pacifici, MD, Garland Herndon professor of medicine and director of the Division of Endocrinology at Emory University School of Medicine. Scientists included Francesco Grassi, Gianluca Tell, Michaela Robbie-Ryan, Yuhao Gao, Masakazu Terauchi, Xiaoying Yang, Milena Romanello, Dean P. Jones, and M. Neal Weitzmann.
"Our research provides important information about the pathway leading from estrogen depletion to bone loss following menopause or removal of ovaries," says Dr. Pacifici. "As we learn more and more about these mechanisms, we come closer to new drug targets that could help prevent this challenging problem that affects millions of women."
The research was supported by the National Institutes of Health. Dr. Grassi also was supported by a Marie-Curie Fellowship from the European Commission.