Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures

Maria, Sifat; Swanson, Mark Herbert; Enderby, Larry T.; D'Amico, Francesco; Enderby, Brianna; Samsonraj, Rebekah M.; Dudakovic, Amel; Wijnen, Andre J. van; Witt-Enderby, Paula A.

doi:10.18632/aging.101158

Cited by 51 publications

(67 citation statements)

References 90 publications

(115 reference statements)

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“…The combination of melatonin and laser irradiation (808 nm, 80 mW, GaAlAs diode) markedly increased the expression of osterix, which promotes the differentiation and mineralization of MC3T3‐E1 cells under hypoxic conditions . Additionally, the combination of melatonin, strontium (citrate), vitamin D3, and vitamin K2 induced osteoblastogenesis, increased BMD, and improved quality of life in postmenopausal osteopenic women (ages 49‐75) …”

Section: Prospects and Conclusionmentioning

confidence: 99%

“…129 Additionally, the combination of melatonin, strontium (citrate), vitamin D3, and vitamin K2 induced osteoblastogenesis, increased BMD, and improved quality of life in postmenopausal osteopenic women (ages . 130 Melatonin also promotes bone formation in some oral diseases, including periodontitis-related bone loss. Periodontitis is an inflammatory condition characterized by gingival inflammation and resorption of alveolar bone.…”

Section: Prospects and Conclusionmentioning

confidence: 99%

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Melatonin: Another avenue for treating osteoporosis?

Jiang

et al. 2019

J Pineal Res

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Melatonin is a signal molecule that modulates the biological circadian rhythms of vertebrates. Melatonin deficiency is thought to be associated with several disorders, including insomnia, cancer, and cardiovascular and neurodegenerative diseases. Accumulating evidence has also indicated that melatonin may be involved in the homeostasis of bone metabolism. Age‐related reductions in melatonin are considered to be critical factors in bone loss and osteoporosis with aging. Thus, serum melatonin levels might serve as a biomarker for the early detection and prevention of osteoporosis. Compared to conventional antiosteoporosis medicines, which primarily inhibit bone loss, melatonin both suppresses bone loss and promotes new bone formation. Mechanistically, by activating melatonin receptor 2 (MT2), melatonin upregulates the gene expression of alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), BMP6, osteocalcin, and osteoprotegerin to promote osteogenesis while inhibiting the receptor activator of NF‐kB ligand (RANKL) pathway to suppress osteolysis. In view of the distinct actions of melatonin on bone metabolism, we hypothesize that melatonin may be a novel remedy for the prevention and clinical treatment of osteoporosis.

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Section: Prospects and Conclusionmentioning

confidence: 99%

Section: Prospects and Conclusionmentioning

confidence: 99%

Melatonin: Another avenue for treating osteoporosis?

Jiang

et al. 2019

J Pineal Res

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“…Melatonin is known to regulate many functions including circadian rhythm, reproduction, temperature, immune system and the cardiovasculature, and therapeutic avenues are being explored for melatonin in the treatment of many diseases . Melatonin has been shown to influence osteoblast functions in vitro and enhance bone regeneration in calvarial defect in explant assays .…”

Section: Introductionmentioning

confidence: 99%

Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway

et al. 2017

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Tryptophan, an essential amino acid through a series of enzymatic reactions gives rise to various metabolites, viz. serotonin and melatonin, that regulate distinct biological functions. We show here that tryptophan metabolism in the pineal gland favors bone mass accrual through production of melatonin, a pineal‐derived neurohormone. Pineal gland‐specific deletion of Tph1, 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 MT1 or MT2 melatonin receptors showed a low bone mass in MT2−/− mice while MT1−/− mice had a normal bone mass compared to the WT mice. This low bone mass in the MT2−/− mice was due to an isolated decrease in osteoblast numbers and bone formation. In vitro assays of the osteoblast cultures derived from the MT1−/− and MT2−/− mice showed a cell intrinsic defect in the proliferation, differentiation and mineralization abilities of MT2−/− osteoblasts compared to WT 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‐induced structural and functional degeneration of bone by specifically increasing bone formation. By identifying pineal‐derived 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.

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“…Strategies to modulate adipose‐derived MSC osteogenesis include the use of osteogenic factors (e.g., bone morphogenic protein, parathyroid hormone) , differentiation agents (dexamethasone, l ‐ascorbate, and glycerol‐2‐phosphate) , and other cocktails (melatonin, strontium, vitamins D and K) . More recently, epigenetic drugs and inhibitors that control the biological fate of human mesenchymal stromal cells have been studied.…”

Section: Introductionmentioning

confidence: 99%

Osteogenic Stimulation of Human Adipose-Derived Mesenchymal Stem Cells Using a Fungal Metabolite That Suppresses the Polycomb Group Protein EZH2

Samsonraj

Dudakovic

Manzar

et al. 2017

Stem Cells Translational Medicine

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Strategies for musculoskeletal tissue regeneration apply adult mesenchymal stem/stromal cells (MSCs) that can be sourced from bone marrow‐ and lipo‐aspirates. Adipose tissue‐derived MSCs are more easily harvested in the large quantities required for skeletal tissue‐engineering approaches, but are generally considered to be less osteogenic than bone marrow MSCs. Therefore, we tested a new molecular strategy to improve their osteogenic lineage‐differentiation potential using the fungal metabolite cytochalasin D (CytoD). We show that CytoD, which may function by redistributing the intracellular location of β‐actin (ACTB), is a potent osteogenic stimulant as reflected by significant increases in alkaline phosphatase activity, extracellular matrix mineralization, and osteoblast‐related gene expression (e.g., RUNX2, ALPL, SPARC, and TGFB3). RNA sequencing analyses of MSCs revealed that acute CytoD treatment (24 hours) stimulates a broad program of osteogenic biomarkers and epigenetic regulators. CytoD decreases mRNA and protein levels of the Polycomb chromatin regulator Enhancer of Zeste Homolog 2 (EZH2), which controls heterochromatin formation by mediating trimethylation of histone 3 lysine 27 (H3K27me3). Reduced EZH2 expression decreases cellular H3K27me3 marks indicating a global reduction in heterochromatin. We conclude that CytoD is an effective osteogenic stimulant that mechanistically functions by blocking both cytoplasmic actin polymerization and gene‐suppressive epigenetic mechanisms required for the acquisition of the osteogenic phenotype in adipose tissue‐derived MSCs. This finding supports the use of CytoD in advancing the osteogenic potential of MSCs in skeletal regenerative strategies. Stem Cells Translational Medicine 2018;7:197–209

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Cited by 51 publications

References 90 publications

Melatonin: Another avenue for treating osteoporosis?

Melatonin: Another avenue for treating osteoporosis?

Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway

Osteogenic Stimulation of Human Adipose-Derived Mesenchymal Stem Cells Using a Fungal Metabolite That Suppresses the Polycomb Group Protein EZH2

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