Division of Pharmaceutical, Administrative and Social Sciences, Duquesne University School of Pharmacy, Pittsburgh, PA, USA.
Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
J Pineal Res. 2018 Apr;64(3). doi: 10.1111/jpi.12465. Epub 2018 Jan 17.
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.
褪黑素骨质疏松预防研究 (MOPS) 表明，每晚使用褪黑素可使绝经后妇女的血清破骨细胞和成骨细胞的平衡比随时间减少。本研究使用人骨髓间充质干细胞 (MSC) 和人外周血单核细胞 (PBMC) 的共培养模型（transwell 或分层）来检查与成骨细胞和成骨细胞比例相关的机制。将褪黑素暴露于成骨 (OS+) 培养基中 21 天的人 MSC/PBMC 共培养物可诱导成骨细胞分化和矿化；然而，只有在分层共培养物中，褪黑素才会抑制破骨细胞生成。褪黑素的作用是通过 MT2 褪黑素受体、MEK1/2 和 MEK5 介导的。在分层而非 transwell 共培养物中，褪黑素通过抑制 RANKL 增加了 OPG:RANKL 比值，表明在成骨过程中与破骨细胞接触会抑制 RANKL 的分泌。褪黑素调节了 ERK1/2、ERK5、β1 整合素、GLUT4 和 IRβ 的表达，这种表达依赖于共培养的类型；然而，在两种培养物中，褪黑素均增加了 RUNX2 并降低了 PPARγ 的表达，这表明代谢过程在控制 MSC 的成骨与成脂细胞命运方面发挥作用。此外，褪黑素对人脂肪来源的 MSC 也具有成骨诱导作用。在体内，给 neu 雌性小鼠饮用水中添加为期一年的每晚 15mg/L 的褪黑素可增加骨中 pErk1/2、pErk5、Runx2 和 Opg 和 Rankl 的水平，这与褪黑素已报道的增强骨作用一致。最后，对 MOPS 的日常日志进行分析表明，与安慰剂相比，接受褪黑素治疗的女性情绪和睡眠质量可能会得到改善。褪黑素的成骨诱导、增强骨作用和改善生活质量表明，褪黑素是一种安全有效的骨质疏松症治疗方法。
