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.

中文翻译：

---

通过松果体衍生的褪黑激素-MT2 受体途径调节骨量。

色氨酸是一种必需氨基酸，通过一系列酶促反应产生各种代谢物，即。血清素和褪黑激素，调节不同的生物功能。我们在这里展示了松果体中的色氨酸代谢有利于通过产生褪黑激素（一种松果体衍生的神经激素）来增加骨量。松果体特异性缺失 Tph1，这是一种催化褪黑激素生物合成第一步的酶，由于骨形成单独减少，而骨吸收参数不受影响，导致褪黑激素水平降低和骨量降低。MT1 或 MT2 褪黑激素受体缺陷小鼠的骨骼分析显示，MT2-/- 小鼠的骨量较低，而 MT1-/- 小鼠的骨量与 WT 小鼠相比正常。MT2-/- 小鼠的这种低骨量是由于成骨细胞数量和骨形成的单独减少。来自 MT1-/- 和 MT2-/- 小鼠的成骨细胞培养物的体外测定显示，与 WT 对应物相比，MT2-/- 成骨细胞的增殖、分化和矿化能力存在细胞内在缺陷，并且突变细胞没有响应褪黑激素的添加。最后，我们证明每天口服褪黑激素可以增加生长过程中的骨骼生长，并且可以通过专门增加骨骼形成来治愈卵巢切除引起的骨骼结构和功能退化。通过识别松果体衍生的褪黑激素作为骨量调节剂通过 MT2 受体，