No Bones About It: Nerve cell protein controls bone formation (Osteoporosis; Neuropeptide Y)
Authors: Beckman Mary 
Published: August 2003

The top dogs in a big corporation might fire the entry-level interns, but they send the pink slips through middle managers. Similarly, when the body's head honcho--the central nervous system--authorizes bone construction, an intermediary neuronal protein delivers the work order, researchers have now found. The results clarify how the obesity-preventing hormone leptin thins bones and also suggest novel approaches for strengthening them. Furthermore, the findings bolster the validity of a new idea: that the brain controls bone metabolism through nerves in addition to the bloodstream.
Animals constantly break down and rebuild their bones to keep their skeletons healthy. The process requires a balance between the actions of cells that destroy and create bone, called osteoclasts and osteoblasts, respectively. When the equilibrium goes awry, diseases such as osteoporosis--in which the skeleton thins, weakens, and cracks--set in. A few years ago, researchers discovered that leptin, which diminishes appetite by spurring other blood-borne molecules into action, also reins in osteoblasts. As a result, rodents that lack leptin develop dense bones. Scientists already knew that the brain emits hormones that ramp osteoclasts up or down. But leptin seemed to control bone growth through the central nervous system (CNS) rather than by dispatching molecules to the tissue through the bloodstream. In the brain, leptin quenches production of a second hormone called neuropeptide Y (NPY). A receptor protein called Y2 binds NPY and coordinates communication between neurons in the CNS, suggesting that it could relay nerve signals between brain and bone.
To examine Y2's role in bone maintenance, Badlock and colleagues engineered a rodent strain that lacked the gene for the receptor. Animals devoid of Y2 had twice the bone mass of normal mice. Without Y2, osteoblasts laid down bone twice as fast as usual, whereas osteoclasts behaved normally. The results suggest that NPY sends a signal through Y2 to slow down bone fabrication.
Next, the researchers probed whether Y2 controls bone growth via the CNS. They selectively removed the Y2 gene from the hypothalamus, a brain region that regulates the body's hormonal systems. Adult animals that lacked Y2 only in the hypothalamus grew thick bones. In addition, the team measured concentrations of hormones known to be affected by leptin. The neuroscientists found no changes in major hormone networks in mice that lack Y2. Together, these results suggest that Y2's influence on bone acts directly through the CNS and does not involve changes in the circulating hormones that leptin alters.
Endocrinologist Gerard Karsenty of Baylor College of Medicine in Houston, Texas, says that this work is an "important verification" for the young theory that the CNS controls bone metabolism. In addition, study leader and neurologist Herbert Herzog of the Garvan Institute of Medical Research in Sydney, Australia, says that Y2 might be an attractive target for new bone disease therapies. Compounds that block Y2 might spur bone growth without also releasing leptin's hold on body weight. That result would be good news for osteoporosis sufferers, who could use a taste of strong bones but without all the fat.
--Mary Beckman

P. A. Badlock, A. Sainsbury, M. Couzens, R. F. Enriquez, G. P. Thomas, E. M. Gardiner, H. Herzog, Hypothalamic Y2 receptors regulate bone formation.
J. Clin. Invest.
109
, 915-921 (2002).
[Abstract]
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