Serotonin Plays Key Role in Bone Loss, Researchers Find

CINCINNATI—A discovery by researchers at the University of Cincinnati (UC) could lead to new understanding of bone loss during lactation and new therapies for bone loss in certain types of cancer.

The researchers, led by Nelson Horseman, PhD, a professor in the department of molecular and cellular physiology, identified serotonin, a neurotransmitter best known for its role in mood, appetite and sleep regulation, as a key component in such bone density loss. They also identified the specific receptor that serotonin acts on in mammary tissue.

Understanding these two findings more deeply could lead to better ways to combat bone loss, potentially by using serotonergic drugs, a UC clinician says.

"These findings could well provide fuel to the development of newer, more effective methods to prevent bone loss or incorporate new bone,” says Elizabeth Shaughnessy, MD, PhD, an associate professor in the department of surgery and UC Health clinician who specializes in the treatment of breast diseases. "Breast cancer patients face this possibility, and not all patients can tolerate the most aggressive therapies currently available.

"Development of therapy with this target in mind could have tremendous potential.”

The findings are published online Feb. 21, 2012, ahead of print in the American Journal of Physiology–Endocrinology and Metabolism,  published by the American Physiological Society.

Co-authors, in addition to Horseman, were Laura Hernandez, PhD, formerly of UC’s molecular and cellular physiology department and now at the University of Wisconsin–Madison, and Karen Gregerson, PhD, an associate professor in UC’s James L. Winkle College of Pharmacy.

"The scientists in our lab have worked very hard to understand the basic biology of the breast,” says Horseman. "It is very gratifying that their work has found a new target that could be used to treat the destruction of bone in breast cancer and other diseases.”

Horseman and his colleagues explored the endocrine secretion of parathyroid hormone related protein (PTHrP), which is secreted by the mammary glands and affects loss of calcium from bones during lactation and soft tissue cancer metastases. Previously, the signal regulating the secretion of PTHrP had been unknown. Through analysis of cells and tissue from mice, cows and people, the researchers identified it as serotonin.

The researchers, aware that many antidepressants that act on serotonin have bone loss as a side effect, found that lactating mice genetically modified to prevent them from making serotonin efficiently had significantly less PTHrP in their mammary glands compared with lactating normal, healthy mice.

Meanwhile, mouse and cow mammary glands treated with serotonin increased expression of PTHrP by eight- and 20-fold, respectively. Treating three human breast cancer cell lines with serotonin also increased PTHrP expression by 20-fold.

The researchers also treated the human breast cancer lines with serotonin to see if it could change a gene called Runx2, which is known to be involved in metastatic breast cancer and bone loss, and found that serotonin increased expression of Runx2.

Finally, the researchers examined mice genetically modified to be missing a particular type of serotonin receptor, as well as mouse mammary cells, to determine which serotonin receptor might be responsible for influencing PTHrP secretion. While previous studies have shown that a serotonin receptor known as 5-HT7 is important for some mammary gland functions, the current study suggests that a different receptor, known as 5-HT2, is the target responsible for stimulating PTHrP levels. (The researchers note that PTHrP was expressed normally in 5-HT7 knockout glands.)

The researchers say their next steps will involve testing of new hypotheses and additional model systems. "With improved knowledge, serotonergic drugs may provide novel opportunities for therapeutic interventions,” they add.

The research was supported by grants from the U.S. Department of Agriculture–National Institute of Food and Agriculture, the Marlene Harris–Ride Cincinnati Foundation, the U.S. Department of Defense and the National Cancer Institute.