Melatonin suppresses bone marrow adiposity in ovariectomized rats by rescuing the imbalance between osteogenesis and adipogenesis through SIRT1 activation

Huang, Xiaoxiong; Chen, Weikai; Gu, Chao; Líu, Hao; Hou, Mingzhuang; Qin, Wanjin; Zhang, Yijian; Chen, Xi; Liu, Tao; Yang, Huilin; He, Fan

doi:10.1016/j.jot.2022.10.002

Cited by 11 publications

(11 citation statements)

References 54 publications

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“…37 However, the intravenous administration of melatonin demonstrated effective prevention of over-accumulation of marrow adipose tissue and protection against bone loss in OVX rats by activating the SIRT1 signaling pathway. 38 Moreover, the growth of capillaries is a crucial factor in the healing of osteoporotic bone defects, as they provide necessary nutrition, oxygen supply, and growth factors. Platelet-derived growth factor-BB has been identified as a potential inducer of angiogenesis in CD31 + and Emcn + endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Gu,

Zhou,

et al. 2023

Journal of Pineal Research

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Osteoporotic bone defects, a severe complication of osteoporosis, are distinguished by a delayed bone healing process and poor repair quality. While bone marrow‐derived mesenchymal stem cells (BMMSCs) are the primary origin of bone‐forming osteoblasts, their mitochondrial function is impaired, leading to inadequate bone regeneration in osteoporotic patients. Melatonin is well‐known for its antioxidant properties and regulation on bone metabolism. The present study postulated that melatonin has the potential to enhance the repair of osteoporotic bone defects by restoring the mitochondrial function of BMMSCs. In vitro administration of melatonin at varying concentrations (0.01, 1, and 100 μM) demonstrated a significant dose‐dependent improvement in the mitochondrial function of BMMSCs obtained from ovariectomized rats (OVX‐BMMSCs), as indicated by an elevation in mitochondrial membrane potential, adenosine triphosphate synthesis and expression of mitochondrial respiratory chain factors. Melatonin reduced the level of mitochondrial superoxide by activating the silent information regulator type 1 (SIRT1) and its downstream antioxidant enzymes, particularly superoxide dismutase 2 (SOD2). The protective effects of melatonin were found to be nullified upon silencing of Sirt1 or Sod2, underscoring the crucial role of the SIRT1‐SOD2 axis in the melatonin‐induced enhancement of mitochondrial energy metabolism in OVX‐BMMSCs. To achieve a sustained and localized release of melatonin, silk fibroin scaffolds loaded with melatonin (SF@MT) were fabricated. The study involved the surgical creation of bilateral femur defects in OVX rats, followed by the implantation of SF@MT scaffolds. The results indicated that the application of melatonin partially restored the mitochondrial energy metabolism and osteogenic differentiation of OVX‐BMMSCs by reinstating mitochondrial redox homeostasis. These findings suggest that the localized administration of melatonin through bone implants holds potential as a therapeutic approach for addressing osteoporotic bone defects.

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Section: Discussionmentioning

confidence: 99%

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Gu,

Zhou,

et al. 2023

Journal of Pineal Research

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“…91 By activating the SIRT1 signaling pathway, melatonin counteracted the differentiation switch from osteogenesis to adipogenesis. 92 In a study on daily effects of melatonin on bone mass of the ovariectomized rats, daytime melatonin administration brought about a greater effect than nighttime administration. 95 In models of aging and diabetes the effects of melatonin resembled that found in ovariectomized rats.…”

Section: Melatonin Activity In Animal Models Of Bone Lossmentioning

confidence: 99%

“…Concerning increases of bone mass and amelioration of bone metabolism in ovariectomized rats, melatonin has remarkable effects on osteogenic differentiation of bone marrow mesenchymal stem cells 91 . By activating the SIRT1 signaling pathway, melatonin counteracted the differentiation switch from osteogenesis to adipogenesis 92 . In a study on daily effects of melatonin on bone mass of the ovariectomized rats, daytime melatonin administration brought about a greater effect than nighttime administration 95 …”

Section: Melatonin Activity In Animal Models Of Bone Lossmentioning

confidence: 99%

Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved

Cardinali

2023

Journal of Pineal Research

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Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c‐peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1–1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.

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“…Importantly, a causal relationship between obesity and lower BMD was confirmed in a two-sample Mendelian randomization study recently ( 21 ). Indeed, increased marrow adiposity is attributed to the shift from osteogenic to adipogenic differentiation of bone marrow mesenchymal stem cells ( 22 ). However, obesity is also positively associated with HU ( 23 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

Relationship between bone mineral density and hyperuricemia in obesity: A cross-sectional study

et al. 2023

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BackgroundObesity is an increasingly severe global public health issue. This study aims to estimate the cross-sectional association between bone mineral density (BMD) and hyperuricemia (HU) in obesity.MethodA total of 275 obese subjects (126 men and 149 women) participated in this cross-sectional study. Obesity was diagnosed as body mass index (BMI) ≥28 kg/m2, whereas HU was defined as the blood uric acid level of 416 μmol/L in men and 360 μmol/L in women. The BMD of the lumbar spine and right hip was measured by dual-energy X-ray absorptiometry (DXA). The multivariable logistic regressions were employed to examine the relationship between BMD and HU in obesity, with the adjustment of gender, age, fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, creatinine, blood urea nitrogen, high-sensitivity C-reactive protein (hs-CRP), cigarette smoking, and alcohol drinking status.ResultThe overall prevalence of HU was 66.9% in this obese population. The mean age and BMI of this population were 27.9 ± 9.9 years and 35.2 ± 5.2 kg/m2, respectively. The multivariable-adjusted OR (the highest vs. lowest BMD quartile) demonstrated a negative relationship between BMD and HU in total (OR = 0.415, 95%CI: 0.182–0.946; p = 0.036), L1 (OR = 0.305, 95%CI: 0.127–0.730; p = 0.008), L2 (OR = 0.405, 95%CI: 0.177–0.925; p = 0.032), and L3 (OR = 0.368, 95%CI: 0.159–0.851; p = 0.020) lumbar vertebrae. In the subgroup analysis for the male population, the BMD was also negatively associated with HU in total (OR = 0.077, 95%CI: 0.014–0.427; p = 0.003), L1 (OR = 0.019, 95%CI: 0.002–0.206; p = 0.001), L2 (OR = 0.161, 95%CI: 0.034–0.767; p = 0.022), L3 (OR = 0.186, 95%CI: 0.041–0.858; p = 0.031), and L4 (OR = 0.231, 95%CI: 0.056–0.948; p = 0.042) lumbar vertebrae. However, such findings did not exist in women. In addition, there was no significant relationship between hip BMD and HU in obesity.ConclusionOur results showed that the lumbar BMD was negatively associated with HU in obesity. However, such findings only existed in men, rather than women. In addition, no significant relationship between hip BMD and HU existed in obesity. Due to the limited sample size and nature of the cross-sectional design, further large prospective studies are still needed to clarify the issues.

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Melatonin suppresses bone marrow adiposity in ovariectomized rats by rescuing the imbalance between osteogenesis and adipogenesis through SIRT1 activation

Cited by 11 publications

References 54 publications

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Melatonin rescues the mitochondrial function of bone marrow‐derived mesenchymal stem cells and improves the repair of osteoporotic bone defect in ovariectomized rats

Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved

Relationship between bone mineral density and hyperuricemia in obesity: A cross-sectional study

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