TY - JOUR
T1 - Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life
T2 - Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis
AU - Maria, Sifat
AU - Samsonraj, Rebekah M.
AU - Munmun, Fahima
AU - Glas, Jessica
AU - Silvestros, Maria
AU - Kotlarczyk, Mary P.
AU - Rylands, Ryan
AU - Dudakovic, Amel
AU - van Wijnen, Andre J.
AU - Enderby, Larry T.
AU - Lassila, Holly
AU - Dodda, Bala
AU - Davis, Vicki L.
AU - Balk, Judy
AU - Burow, Matt
AU - Bunnell, Bruce A.
AU - Witt-Enderby, Paula A.
N1 - Publisher Copyright:
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - GLUT4
KW - MEK1/2
KW - MEK5
KW - MT2 melatonin receptor
KW - PPARγ
KW - adipocytes
KW - melatonin
KW - mesenchymal stem cells
KW - osteoblasts
KW - osteoclasts
UR - http://www.scopus.com/inward/record.url?scp=85040798562&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040798562&partnerID=8YFLogxK
U2 - 10.1111/jpi.12465
DO - 10.1111/jpi.12465
M3 - Article
C2 - 29285799
AN - SCOPUS:85040798562
SN - 0742-3098
VL - 64
JO - Journal of Pineal Research
JF - Journal of Pineal Research
IS - 3
M1 - e12465
ER -