Sci. Aging Knowl. Environ., 3 November 2004
Molecule transmits estrogen's bone-saving signal through T cells
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/44/nf98
In many companies, the CEO snags the press, but it's the mailroom employee who keeps things running smoothly. New research reveals how an unsung cellular hero similarly helps estrogen accomplish its famous bone-saving achievements. The result reveals a crucial step in the bone-preserving chain of command and might point researchers toward new ways of bolstering bone in older women.
When estrogen amounts wane after menopause, bones frequently thin, a condition known as osteoporosis (see "The Plot Thickens on Thin Bones"). Estrogen supplements strengthen bone, but the therapy heightens the risk of other health problems such as breast cancer and heart disease (see "Weathering the HRT Storm"). Researchers want to understand how estrogen shores up the skeleton in order to find other ways of reinforcing weakening bones. Two teams of cells play off each other to maintain the skeleton. Osteoclasts dissolve old bone, and osteoblasts construct new bone to replace it. When construction and destruction balance, the skeleton stays robust. But if osteoclasts overwhelm osteoblasts, osteoporosis ensues. In previous work, bone researcher Roberto Pacifici of Emory University in Atlanta, Georgia, and colleagues found that removing rodent ovaries--and thereby depleting estrogen and bone--boosts the number of T cells that generate an inflammatory molecule, TNF-. This molecule prods the bone marrow to make osteoclasts. But no one knew how estrogen loss causes T cells to multiply.
Estrogen stimulates production of a signaling molecule called TGF-, which can block cell division. So Pacifici and colleagues investigated whether estrogen quells T cell formation by sparking the TGF- pathway. The team engineered mice so that their T cells produce a defective form of the TGF- receptor protein that quenches the TGF- signal. The animals had unusually thin bones and made more T cells than did normal animals. Next, the researchers removed the rodents' ovaries. Mice with and without ovaries lost bone equally fast, suggesting that estrogen's bone-preserving talents operate through TGF-.
To investigate whether augmenting TGF- amounts would protect the skeletons of mice without ovaries, the researchers injected normal animals with a TGF--producing gene and then removed the ovaries from some of them. The gene therapy slowed bone loss in rodents without ovaries and had no effect on animals that retained the organs.
"The science in this paper is really excellent," says bone researcher Steven Teitelbaum of Washington University in St. Louis, Missouri. "They show that the way estrogen blocks [bone loss] is by induction of TGF-." However, many questions remain. For instance, previous studies revealed that augmenting TGF- in bone cell precursors speeds osteoclast formation. Perhaps when TGF- amounts are large, the direct action on osteoclasts overrides an indirect effect through T cells, Teitelbaum speculates. Endocrinologist Stavros Manolagas of the University of Arkansas for Medical Sciences in Little Rock says that many signals regulate bone-building and bone-breaking cells, and researchers must weigh them all when deciphering estrogen's power over the skeleton; T cells are unlikely to be the whole story. Delving further into these questions might reveal how to prod cellular workers to save bone--even when the boss is gone.
November 3, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150