Mouse Studies Reveal Immune Mechanism Involved in Bone Loss Caused
by Estrogen Deficiency
If Confirmed in Humans, Discovery Could Lead to Prevention Strategies
for Postmenopausal Bone Loss
ATLANTA- Scientists have uncovered in mice a key mechanism of the immune
system involved in the bone loss that results from estrogen deficiency.
If confirmed in human studies, the findings would demonstrate that postmenopausal
osteoporosis is the result of an inappropriate immune response triggered
by estrogen deficiency. The research also could help explain why estrogen
deficiency appears to exacerbate autoimmune diseases, such as rheumatoid
Results of the research will be published in the online edition of the
Proceedings of the National Academy of Sciences the week of August 4.
The study’s senior author was Roberto Pacifici, MD, professor of medicine
and director of the Division of Endocrinology at Emory University School
of Medicine. Lead author was Simone Cenci, MD, now at the San Raffaele
Scientific Institute in Milan, Italy. Other authors included Gianluca
Toraldo and Oscar Sierra from Washington University School of Medicine
and Barnes-Jewish Hospital in St. Louis, and M. Neale Weitzman, Cristiana
Roggia and Wei Ping Qian from Emory School of Medicine.
Scientists already had discovered that bone loss caused by estrogen
deficiency results from the overexpansion of T cells in the immune system.
Immune T cells are known to produce a protein called tumor necrosis
factor (TNF) that increases the formation of osteoclasts in rodents
and humans cells that help cause the absorption and removal of bone.
T cell proliferation is typically caused by the activation of T cells,
but until now scientists have not understood exactly why and how estrogen
deficiency causes the T cells to become activated.
In order to model postmenopausal estrogen deficiency, the scientists
removed the ovaries from mice, then studied the mouse T cells in culture.
They confirmed that T cell activation was jump started by the immune
regulatory protein interferon gamma (IFN-y), which in turn stimulated
a protein called class II transactivator (CIITA). They found that increased
expression of CIITA leads to expanded antigen presentation by macrophages
immune cells that alert T cells to the presence of invading organisms
and enhanced T cell activation in the bone marrow and extended T-cell
lifespan. IFN-y has previously been implicated as an activator of aberrant
immune expression in autoimmune diseases.
"This study represents a major advance in our understanding of the mechanism
of action of estrogen in bone, including the essential link between
the immune system and bone stability," said Dr. Pacifici. "If we observe
the same results in humans, this could lead to the development of new
drugs that work in bone like estrogen, but do not have negative effects
on reproductive organs and the cardiovascular system. The study also
helps explain why certain autoimmune diseases, such as rheumatoid arthritis,
are improved by estrogen and exacerbated by menopause."
The research was supported by the National Institutes of Health, the
Eastern Missouri Chapter of the Arthritis Foundation and the Lilly Center
for Women’s Studies.