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We show here that tryptophan metabolism in the pineal gland favors bone mass accrual through production of melatonin, a pineal\u2010derived neurohormone. Pineal gland\u2010specific deletion of\n                    <jats:italic>Tph1<\/jats:italic>\n                    , 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\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      1\n                    <\/jats:italic>\n                    or\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      2\n                    <\/jats:italic>\n                    melatonin receptors showed a low bone mass in\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      2\u2212\/\u2212\n                    <\/jats:italic>\n                    mice while\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      1\u2212\/\u2212\n                    <\/jats:italic>\n                    mice had a normal bone mass compared to the\n                    <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>\n                    mice. This low bone mass in the\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      2\u2212\/\u2212\n                    <\/jats:italic>\n                    mice was due to an isolated decrease in osteoblast numbers and bone formation. In vitro assays of the osteoblast cultures derived from the\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      1\u2212\/\u2212\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      2\u2212\/\u2212\n                    <\/jats:italic>\n                    mice showed a cell intrinsic defect in the proliferation, differentiation and mineralization abilities of\n                    <jats:italic>\n                      <jats:styled-content style=\"fixed-case\">MT<\/jats:styled-content>\n                      2\u2212\/\u2212\n                    <\/jats:italic>\n                    osteoblasts compared to\n                    <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>\n                    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\u2010induced structural and functional degeneration of bone by specifically increasing bone formation. By identifying pineal\u2010derived 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.\n                  <\/jats:p>","DOI":"10.1111\/jpi.12423","type":"journal-article","created":{"date-parts":[[2017,5,17]],"date-time":"2017-05-17T02:53:16Z","timestamp":1494989596000},"source":"Crossref","is-referenced-by-count":103,"title":["Regulation of bone mass through pineal\u2010derived melatonin\u2010\n                    <scp>MT<\/scp>\n                    2 receptor pathway"],"prefix":"10.1111","volume":"63","author":[{"given":"Kunal","family":"Sharan","sequence":"first","affiliation":[{"name":"Systems Biology of Bone Department of Mouse and Zebrafish Genetics Wellcome Trust Sanger Institute  Cambridge 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