Abstract
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.
Highlights
Skeleton is one of the largest organ systems in the vertebrate body and performs multiple mechanical, hematopoietic and endocrine functions.[1]
Results show that ablation of melatonin synthesis in the pineal gland or its MT2 receptors in the bone leads to a low bone mass phenotype due to an isolated defect in the bone formation
Inactivation of the MT2 and not the melatonin receptor 1A (MT1) receptors leads to a cell intrinsic defect in the osteoblasts ability to proliferate, differentiate and deposit new bone matrix
Summary
Skeleton is one of the largest organ systems in the vertebrate body and performs multiple mechanical, hematopoietic and endocrine functions.[1]. Histological and histomorphometric analysis of skeleton at 12 weeks of age revealed that mice lacking Tph[1] in the pineal on the melatonin-proficient C3H/HeJ background (Tph1pineal−/−) developed a low bone mass phenotype secondary to a decrease in osteoblast numbers and bone formation rate, while bone resorption parameters were not affected compared to +/+ mice (Figure 1C and Fig. S1C,D). Femur samples from untreated and melatonin-treated OVX mice were subjected to a three-point bending test and a compression analysis, to determine stiffness and maximal load (Figure 4H,I) Both parameters that were decreased after ovariectomy were restored, completely, in OVX mice treated with melatonin at 100 mg/kg/d treatment to the values seen in sham-o perated mice (Figure 4H,I). Daily oral administration of melatonin could revert the bone loss, architectural deterioration and lost bone quality caused by a long-term gonadal failure in mice through a major increase in bone formation
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