UB Scientists Discover Role of Melatonin in Bone Formation

BUFFALO, N.Y. -- University at Buffalo researchers have shown for the first time that melatonin, a hormone produced naturally by the pineal gland and used widely as a supplement to diminish jet lag and improve sleep patterns, may play an important role in promoting bone growth.

Results of the research appeared recently in the Journal of Biological Chemistry. The study was conducted by Jerome A. Roth, Ph.D., professor of pharmacology and toxicology in the UB School of Medicine and Biomedical Sciences, and Moon-Il Cho, Ph.D., professor of oral biology in the UB School of Dental Medicine.

By exposing mouse pre-osteoblasts and fully differentiated rat osteoblasts -- cells that produce and mineralize bone matrix components -- to melatonin, the researchers were able to show that normal body levels of the hormone speeded up the transformation of pre-osteoblasts to fully-differentiated osteoblasts, and induced both types of cells to produce increased amounts of several bone matrix proteins responsible for bone formation.

"After binding to its receptor on the cell surface, melatonin signals the cell to produce and mineralize bone matrix proteins," Roth said. "This has not been shown before. We are now investigating what cellular events are taking place to make this happen."

"We know melatonin decreases with age, and that bone loss, which can lead to osteoporosis, is an inevitable part of aging, especially among women," Cho said. "Can melatonin help prevent osteoporosis? Our research indicates it may have that potential."

Roth said human melatonin receptors are very similar to rat and mouse melatonin receptors, a characteristic that makes these cells a good model for human osteoblasts.

While the mechanism that allows melatonin to have an effect on bone formation is still

unclear, the UB researchers hypothesize it may involve an intracellular second messenger called cyclic AMP.

"We know that receptors for melatonin are coupled to adenylcyclase, an enzyme responsible for the formation of cyclic AMP, and we know that cyclic AMP inhibits pre-osteoblast differentiation. We think melatonin has the ability to inhibit the action of cyclic AMP and, consequently, to trigger cell differentiation."

Under standard growth conditions in vitro, mouse pre-osteoblasts undergo cell differentiation to osteoblasts and mineralization in 21 days. Roth and Cho showed that in the presence of melatonin, cell differentiation was completed by day 12 and was equivalent or greater at that point than cells grown for 21 days.

Melatonin also increased expression of bone sialoprotein, or BSP, and other bone-marker matrix proteins such as secreted protein, which is acidic and rich in cycteine, known as SPARC; osteocalcin, and alkaline phosphatase, or ALP, the researchers found.

Most significantly, said Roth, further experiments showed that the mouse pre-osteoblasts responded to normal body levels of melatonin, but the cells needed to undergo five to seven days of differentiation before they were capable of responding to melatonin at that level.

The fully-differentiated rat osteoblasts responded rapidly to normal body melatonin levels, showing increased expression of the bone marker proteins BSP and osteocalcin within one hour of exposure to the hormone, the researchers found.

"These findings place melatonin with a select handful of other agents, including glucocorticoids, bone morphogenic proteins and vitamin D, that are known to stimulate mineralization in osteoblasts," the researchers stated. "Because melatonin levels decrease during the aging process, the possibility must be considered that melatonin may have a significant influence on the rate of synthesis and maintenance of bone in the elderly."

Additional researchers involved in this work were Byung-Gook Kim, D.D.S., Ph.D., a Korean visiting scholar, and Wen-Lang Lin, Ph.D., technical specialist, both in the Department of Oral Biology in the UB School of Dental Medicine.

The research was supported by grants from the National Institutes of Health, the Environmental Protection Agency and UB.