The hormone leptin, which is well known for regulation of body weight as an anorexigenic factor, also plays a central role in the regulation of bone formation. In the 1 November issue of Cell, new work has identified the mediator of this action of leptin and points toward a therapeutically useful way of manipulating this pathway to increase bone mass. Osteoporosis is a degenerative bone disease that affects many millions of women, especially after menopause, causing bones to lose mass, so that they become brittle and prone to fracture. Drugs are available that can arrest the bone destruction caused by osteoporosis, but none can increase bone formation or reverse the effects of bone damage.

Leptin is known to be an anti-osteogenic factor — a powerful inhibitor of bone formation. Previous studies have shown that mice lacking leptin are not only extremely obese, but also have a greater bone mass than normal mice. However, that it is leptin signalling rather than body weight that controls bone mass is seen from the analysis of fat-free mice that have no adipocytes, the cell type that produces leptin. Fat-free mice that are lean have the same high-bone-mass phenotype as mice deficient in leptin.

In this study, Karsenty and colleagues have characterized the mechanism by which leptin regulates bone mass, and they show that the sympathetic nervous system is the intermediate between leptin and osteoblasts, and that this mode of action does not affect body weight. The sympathetic nervous system regulates stress responses, such as increasing heart rate, blood pressure and respiratory rate; it also stimulates endocrine glands such as the adrenal and the thyroid to produce the hormones adrenaline and cortisol, respectively. Studies in mice show that neuropeptides that mediate anorexigenic functions and regulate body weight do not affect bone formation. In addition, it was found that anti-osteogenic signals are transmitted through G-protein-coupled β-adrenoceptors on osteoblasts. In wild-type and leptin-deficient mice, β-adrenoceptor agonists decreased bone mass, whereas in wild-type and ovarectomized 'menopausal' mice β-adrenoceptor antagonists increased bone mass.

This research suggests that β-blockers, drugs that are used routinely to treat high blood pressure, could also help reverse osteoporosis. But does this regulatory pathway operate in humans as well as mice? There is evidence indicating that the sympathetic nervous system has a role in the regulation of human bone mass, but further studies in rats and with humans will be needed for confirmation.