'Clock' Genes Mediate Leptin Effects On Bone Formation

"We found that the clock genes are acting in bone cells to mediate the action of the brain on bone formation," said Dr. Gérard Karsenty, professor in the department of molecular and human genetics at BCM. "There is a clock in bone, and the clock is there to control bone formation."

In a series of previous studies, Karsenty and his colleagues identified the hormone leptin as a critical regulator of bone mass. To achieve this function following its binding to hypothalamic receptors, leptin uses the sympathetic nervous system as a peripheral mediator to control bone formation. The mechanisms whereby sympathetic tone controlled bone formation in bone cells was still unknown.

In the present studies Karsenty and his colleagues demonstrated that genes of the molecular clock are expressed in bone cells, that their expression in these cells is regulated by leptin and the sympathetic tone, and that mice that have a disrupted molecular clock have a high bone mass but not other abnormalities usually associated with leptin deficiency such as obesity and sterility.

In previous studies, when Karsenty and his colleagues infused leptin into the brain, bone mass and bone formation decreased.

"To our surprise when we infuse leptin into the brains of mice with no clock genes, the mice had high bone mass, establishing that the clock genes are operating downstream (or after) of leptin presumably in bone cells," said Karsenty. Indeed, removing clock genes from bone cells results in an increase in bone formation. This work is the first in vivo demonstration that the molecular clock affects bone physiology.

"What is remarkable in terms of leptin biology is that the genes of the molecular clock are expressed in other cell types affected by leptin, yet the mutant mice we analyzed are, on a normal diet, lean and fertile, their only abnormality is to have to make too much bone," said Karsenty.

Leptin's role in appetite control has garnered much scientific and popular attention, but Karsenty's work demonstrates that the hormone's primary or at least ancestral role may have been to control bone mass, a function that was required during evolution before controlling appetite."

Others who participated in this research include Drs. Loning Fu and Millan S. Patel of BCM, Dr. Allan Bradley of the Wellcome Trust Institute Wellcome Genome Campus in Cambridge, England, and Dr. Erwin F. Wagner of the Research Institute of Molecular Pathology in Vienna, Austria. This work was supported by the U.S. National Institutes of Health and a Canadian Institutes for Health Research Fellowship.