Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway.

Tryptophan, an essential amino acid through a series of enzymatic reactions gives
rise to various metabolites, viz. serotonin and melatonin, that regulate distinct biological
functions. We show here that tryptophan metabolism in the pineal gland favors
bone mass accrual through production of melatonin, a pineal-derived
neurohormone. Pineal gland-specific
deletion of Tph1, the enzyme that catalyzes the
first step in the melatonin biosynthesis lead to a decrease in melatonin levels and a
low bone mass due to an isolated decrease in bone formation while bone resorption
parameters remained unaffected. Skeletal analysis of the mice deficient in MT1 or
MT2 melatonin receptors showed a low bone mass in MT2−/− mice while MT1−/−
mice had a normal bone mass compared to the WT mice. This low bone mass in the
MT2−/− mice was due to an isolated decrease in osteoblast numbers and bone formation.
In vitro assays of the osteoblast cultures derived from the MT1−/− and
MT2−/− mice showed a cell intrinsic defect in the proliferation, differentiation and
mineralization abilities of MT2−/− osteoblasts compared to WT counterparts, and
the mutant cells did not respond to melatonin addition. Finally, we demonstrate that
daily oral administration of melatonin can increase bone accrual during growth and
can cure ovariectomy-induced
structural and functional degeneration of bone by specifically
increasing bone formation. By identifying pineal-derived
melatonin as a
regulator of bone mass through MT2 receptors, this study expands the role played by
tryptophan derivatives in the regulation of bone mass and underscores its therapeutic
relevance in postmenopausal osteoporosis.