Sci. Aging Knowl. Environ., 13 September 2005
Circadian clock teams with appetite-suppressing hormone to temper bone growth
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/37/nf73
Television commercials implore viewers to drink milk every day for strong bones, but new research provides a different connection between daily activities and a robust skeleton. An appetite-dampening hormone impinges on cogs in the body's internal clock to slow bone growth, the findings show. The work reveals a new body process controlled by the clock and bolsters connections between circadian rhythms and metabolism.
Circadian clock proteins govern a variety of body processes whose tempos vary over 24-hour periods, such as sleep and heartbeat. Bone remodeling--in which tired bone is replaced by fresh material--also waxes and wanes during the course of a day; generally, an organism repairs bone while resting. Fu and colleagues investigated whether the circadian clock influences skeletal renovations.
The researchers raised two lines of mice that lack particular components of the circadian clock. Both types of rodents had approximately 50% more bone mass at 24 weeks of age than did normal mice. Additional studies revealed that the animals' bone-dissolving cells--called osteoclasts--worked at a normal pace. But their bone builders--osteoblasts--toiled extra hard. These findings suggest that the circadian clock normally limits bone construction.
Previously, the researchers had found that mice without leptin, a hormone that suppresses appetite, also have hefty bones (see "The Plot Thickens on Thin Bones"). Because leptin activity cycles during the day, the circadian clock might influence bone growth by altering leptin quantities, the researchers conjectured. Mice with defective clocks, however, bore normal leptin quantities in their blood. In addition, injecting leptin into the animals didn't decrease bone mass as it did in normal animals. That finding suggests that leptin acts in the same pathway as the clock proteins do, but upstream rather than downstream of them.
The brain houses the master clock, but most tissues also hold their own clocks. The researchers found that mice with defective osteoblast clocks but with intact central clocks still had unusually massive bones. In addition, clock-defective osteoblasts contained larger quantities of proteins that encourage bone-cell reproduction than did normal bone cells; animals with glitches in leptin circuitry held similarly altered osteoblasts. Together, the findings suggest that leptin stems bone formation by activating a circadian clock in bone cells, which dampens bone-building activity.
Showing that components of the circadian clock influence bone growth is new, says neurobiologist Fred Turek of Northwestern University in Chicago, Illinois. The paper "hits home one more time that circadian clock genes are all over the body," he adds. The leptin connection also strengthens ties between metabolism and circadian rhythms, he says. Mice with faulty clocks are obese, for example. Chronobiologist Andries Kalsbeek of the Netherlands Brain Research Institute in Amsterdam says that shifts in circadian patterns in the elderly could foster osteoporosis, although other factors--such as hormonal changes--might be more important. Brain neurons combine signals from the central clock, leptin, estrogen, and other molecules to control organs throughout the body. Next, researchers should figure out how the signals fit together to determine whether the skeleton grows or shrinks, says Kalsbeek. Putting leptin, bone, and the circadian clock together should whet researchers' appetites to understand how to keep the skeleton strong.
September 14, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150