The Melatonin Osteoporosis Prevention Study (MOPS) demonstrated that nightly melatonin resulted in a time‐dependent decrease in equilibrium ratios of serum osteoclasts and osteoblasts in perimenopausal women. This study examines mechanisms related to the ratios of osteoblasts and osteoclasts using coculture models (transwell or layered) of human mesenchymal stem cell (MSC) and human peripheral blood monocytes (PBMCs). Human MSC/PBMC cocultures exposed to melatonin in osteogenic (OS+) medium for 21 days induced osteoblast differentiation and mineralization; however, only in layered cocultures did melatonin inhibit osteoclastogenesis. Melatonin effects were mediated through MT2 melatonin receptors, MEK1/2, and MEK5. In layered but not transwell cocultures, melatonin increased OPG:RANKL ratios by inhibiting RANKL, suggesting that contact with osteoclasts during osteoblastogenesis inhibits RANKL secretion. Melatonin modulated expression of ERK1/2, ERK5, β1 integrin, GLUT4, and IRβ that was dependent upon the type of coculture; however, in both cultures, melatonin increased RUNX2 and decreased PPARγ expression, indicating a role for metabolic processes that control osteogenic vs adipogenic cell fates of MSCs. Furthermore, melatonin also has osteoblast‐inducing effects on human adipose‐derived MSCs. In vivo, one‐year nightly melatonin (15 mg/L) given to neu female mice in their drinking water increased pErk1/2, pErk5, Runx2, and Opg and Rankl levels in bone consistent with melatonin's already reported bone‐enhancing effects. Finally, analysis of daily logs from the MOPS demonstrated a significant improvement in mood and perhaps sleep quality in women receiving melatonin vs placebo. The osteoblast‐inducing, bone‐enhancing effects of melatonin and improvement in quality of life suggest that melatonin is a safe and effective bone loss therapy.

中文翻译：

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褪黑素对成骨细胞/破骨细胞共培养，骨骼和生活质量的生物学影响：褪黑激素介导的成骨细胞生成中MT2褪黑素受体，MEK1 / 2和MEK5的作用

褪黑激素骨质疏松症预防研究（MOPS）表明，夜间褪黑激素导致围绝经期妇女的血清破骨细胞和成骨细胞的平衡比呈时间依赖性下降。这项研究使用人间充质干细胞（MSC）和人外周血单核细胞（PBMC）的共培养模型（跨孔或分层）研究了与成骨细胞和破骨细胞比率有关的机制。将人类MSC / PBMC共培养物在成骨（OS +）培养基中暴露于褪黑素21天会诱导成骨细胞分化和矿化；然而，仅在分层共培养中，褪黑激素才抑制破骨细胞生成。褪黑激素的作用是通过MT2褪黑激素受体，MEK1 / 2和MEK5介导的。在分层但非跨孔共培养中，褪黑素可通过抑制RANKL来增加OPG：RANKL的比率，提示在成骨细胞生成过程中与破骨细胞接触会抑制RANKL分泌。褪黑素调节ERK1 / 2，ERK5，β1整合素，GLUT4和IRβ的表达，这取决于共培养的类型。但是，在两种培养物中，褪黑素均会增加RUNX2并降低PPARγ表达，这表明在控制MSC成骨和成脂细胞命运的代谢过程中发挥了作用。此外，褪黑激素还对人脂肪来源的MSC具有成骨细胞诱导作用。在体内，每天服用1次每晚褪黑激素（15 mg / L）表明代谢过程在控制MSC的成骨性和成脂性细胞命运方面发挥了作用。此外，褪黑激素还对人脂肪来源的MSC具有成骨细胞诱导作用。在体内，每天服用1次每晚褪黑激素（15 mg / L）表明代谢过程在控制MSC的成骨性和成脂性细胞命运方面发挥了作用。此外，褪黑激素还对人脂肪来源的MSC具有成骨细胞诱导作用。在体内，每天服用1次每晚褪黑激素（15 mg / L）neu雌性小鼠的饮用水中增加了pErk1 / 2，pErk5，Runx2以及骨骼中Opg和Rankl的水平，这与褪黑素已经报道的增强骨骼的作用相一致。最后，对来自MOPS的每日日志的分析表明，接受褪黑激素和安慰剂的女性在情绪上和睡眠质量上都有显着改善。褪黑激素的成骨​​诱导，骨骼增强作用和生活质量的改善表明，褪黑激素是一种安全有效的骨质流失疗法。