Sci. Aging Knowl. Environ., 17 March 2004
Greasing the Way for Bone Growth
Signaling molecule steers cells toward bone and away from fat
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/11/nf30
BANFF, CANADA--Healthy bodies keep fat thin and bones thick, and new research presented here 5 March 2004 at the Adipogenesis and Obesity Keystone Symposium reveals one way to achieve that goal. A single molecule sparks a signaling pathway that encourages bone formation and curtails corpulence. The work suggests that defects in the molecule might underlie a metabolic transition that occurs during aging, perhaps pointing the way toward new bone-strengthening therapies.
Obesity soars among the elderly, who also often lose bone. Some observations suggest that the two processes are linked. For instance, when skeletons thin, fat accumulates in bone marrow. Studies seeking the molecular players that bolster bone have implicated a protein-signaling cascade that's activated by Wnt proteins. Glitches in a cell-surface protein that grabs Wnt molecules underlie a human disease characterized by fragile bones (see "Skeleton Crew"), for example. And crippling a protein that blocks the Wnt signal stems age-related bone loss in mice (see "For Wnt of Bone"). The pathway also appears to restrain fat-cell specialization; blocking the signal encourages precursor cells to morph into fat. Mammals carry numerous Wnt proteins, and researchers weren't sure whether one of them transmits both messages.
Molecular physiologist Ormond MacDougald and colleagues at the University of Michigan, Ann Arbor, keyed on Wnt10b, which fat-cell precursors produce in abundance. The protein disappears when the cells are exposed to a mixture of chemicals that promotes specialization, suggesting that it might clamp down on fat-cell development. To explore this idea and test whether the molecule also spurs bone growth, the researchers hiked Wnt10b production in mouse bone-marrow cells, which can develop into either bone or fat cells. Augmented animals bore half as much fat as unaltered rodents did and cleared glucose from their blood more quickly, a sign of healthy metabolism that often deteriorates with obesity. The extra gene also overpowered a genetic propensity toward tubbiness, trimming fat and improving blood-sugar control in two lines of mice with mutations that usually make them pudgy. Next, the team examined the animals' bones. Rodents with extra Wnt10b had thicker, stronger bones than controls did. Together, the results support the idea that Wnt10b steers impressionable marrow cells to form bone rather than fat. If the protein falters, animals suffer a double whammy: thin bones and extra blubber. Other researchers have found that Wnt10b quantities drop with age, at least in some cell types, says MacDougald, and this change might help explain why the elderly swap bone for fat.
"The notion that [Wnt]10b is making the switch between bone and fat is an intriguing one," says fat cell researcher Stephen Farmer of Boston University Medical Center. Researchers have identified other signals that prompt bone formation and block fat production, says Farmer, and future work should address how those signals mesh with Wnt. Bone researchers are especially interested in how organisms balance fat- and bone-cell production, he notes. Coaxing fat cells to become bone cells might provide a new tool for treating patients with osteoporosis to fatten up their thin skeletons.
March 17, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150