Journal
JOURNAL OF PINEAL RESEARCH
Volume 64, Issue 3, Pages -Publisher
WILEY
DOI: 10.1111/jpi.12465
Keywords
adipocytes; GLUT4; MEK1/2; MEK5; melatonin; mesenchymal stem cells; MT2 melatonin receptor; osteoblasts; osteoclasts; PPAR gamma
Categories
Funding
- National Institute for Arthritis and Musculoskeletal Diseases [NIAMS R15 AR068605, NIAMS R01 AR049069]
- Susan G. Komen for the Cure Duquesne University Translational Research
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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 21days 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, 1 integrin, GLUT4, and IR that was dependent upon the type of coculture; however, in both cultures, melatonin increased RUNX2 and decreased PPAR 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 (15mg/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.
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