Rapamycin could increase the effects of melatonin against age-dependent bone loss

Tao, Zhou-Shan; Lu, Han-Li; Ma, Nengfeng; Zhang, Rou-Tian; Yang, Li; Yang, Min; Xu, Huazi

doi:10.1007/s00391-019-01659-4

Cited by 12 publications

(7 citation statements)

References 34 publications

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“…no. C0875, Sigma) at 10 and 3 days before the end of the experiment ( 32 ). At the end of the observation time (4 weeks after the treatment), the tibia samples were obtained for hard-tissue slicing and then imaged through the laser confocal microscopy (LSM 880, Zeiss, Germany).…”

Section: Methodsmentioning

confidence: 99%

Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling

et al. 2022

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Previous studies have revealed that melatonin could play a role in anti-osteoporosis and promoting osteogenesis. However, the effects of melatonin treatment on osteoporotic bone defect and the mechanism underlying the effects of melatonin on angiogenesis are still unclear. Our study was aimed to investigate the potential effects of melatonin on angiogenesis and osteoporotic bone defect. Bone marrow mesenchymal stem cells (BMSCs) were isolated from the femur and tibia of rats. The BMSC osteogenic ability was assessed using alkaline phosphatase (ALP) staining, alizarin red S staining, qRT-PCR, western blot, and immunofluorescence. BMSC-mediated angiogenic potentials were determined using qRT-PCR, western blot, enzyme-linked immunosorbent assay, immunofluorescence, scratch wound assay, transwell migration assay, and tube formation assay. Ovariectomized (OVX) rats with tibia defect were used to establish an osteoporotic bone defect model and then treated with melatonin. The effects of melatonin treatment on osteoporotic bone defect in OVX rats were analyzed using micro-CT, histology, sequential fluorescent labeling, and biomechanical test. Our study showed that melatonin promoted both osteogenesis and angiogenesis in vitro. BMSCs treated with melatonin indicated higher expression levels of osteogenesis-related markers [ALP, osteocalcin (OCN), runt-related transcription factor 2, and osterix] and angiogenesis-related markers [vascular endothelial growth factor (VEGF), angiopoietin-2, and angiopoietin-4] compared to the untreated group. Significantly, melatonin was not able to facilitate human umbilical vein endothelial cell angiogenesis directly, but it possessed the ability to promote BMSC-mediated angiogenesis by upregulating the VEGF levels. In addition, we further found that melatonin treatment increased bone mineralization and formation around the tibia defect in OVX rats compared with the control group. Immunohistochemical staining indicated higher expression levels of osteogenesis-related marker (OCN) and angiogenesis-related markers (VEGF and CD31) in the melatonin-treated OVX rats. Then, it showed that melatonin treatment also increased the bone strength of tibia defect in OVX rats, with increased ultimate load and stiffness, as performed by three-point bending test. In conclusion, our study demonstrated that melatonin could promote BMSC-mediated angiogenesis and promote osteogenesis–angiogenesis coupling. We further found that melatonin could accelerate osteoporotic bone repair by promoting osteogenesis and angiogenesis in OVX rats. These findings may provide evidence for the potential application of melatonin in osteoporotic bone defect.

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Section: Methodsmentioning

confidence: 99%

Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling

et al. 2022

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“…Thus, even at a low dose, melatonin appears to be effective against osteoporosis. Some preclinical evidence suggests that the addition of rapamycin enhances the anti-osteoporotic effects of melatonin in age-dependent osteoporosis [67]. In OVX rats, melatonin combined with rapamycin was more effective than melatonin alone in improving osteoporotic bone microarchitecture and bone quality and strength [67].…”

Section: Mc3t3-e1 Cells 1 µM Culturementioning

confidence: 99%

“…Some preclinical evidence suggests that the addition of rapamycin enhances the anti-osteoporotic effects of melatonin in age-dependent osteoporosis [67]. In OVX rats, melatonin combined with rapamycin was more effective than melatonin alone in improving osteoporotic bone microarchitecture and bone quality and strength [67]. The beneficial effects of melatonin on age-dependent bone loss were achieved through regulation of the osteoprotegerin (OPG)/RANKL signaling pathway [67].…”

Section: Mc3t3-e1 Cells 1 µM Culturementioning

confidence: 99%

Melatonin Inhibits Osteoclastogenesis and Osteolytic Bone Metastasis: Implications for Osteoporosis

MacDonald

Tsai

Chang³

et al. 2021

IJMS

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Osteoblasts and osteoclasts are major cellular components in the bone microenvironment and they play a key role in the bone turnover cycle. Many risk factors interfere with this cycle and contribute to bone-wasting diseases that progressively destroy bone and markedly reduce quality of life. Melatonin (N-acetyl-5-methoxy-tryptamine) has demonstrated intriguing therapeutic potential in the bone microenvironment, with reported effects that include the regulation of bone metabolism, acceleration of osteoblastogenesis, inhibition of osteoclastogenesis and the induction of apoptosis in mature osteoclasts, as well as the suppression of osteolytic bone metastasis. This review aims to shed light on molecular and clinical evidence that points to possibilities of melatonin for the treatment of both osteoporosis and osteolytic bone metastasis. It appears that the therapeutic qualities of melatonin supplementation may enable existing antiresorptive osteoporotic drugs to treat osteolytic metastasis.

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“…Afterwards, thin sections (about 50μm in thickness) were prepared using the diamond saw (Leica Microtome, Wetzlar, Germany). Calcein double labelling in undecalci ed bone slices were observed under a uorescence microscope(FLUOVIEW FV300, Olympus) to quantify the bone mineralization as previously described [23,24].…”

Section: Histomorphometric Analysismentioning

confidence: 99%

Intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats

Tao

Zhou

et al. 2021

European Journal of Pharmacology

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Objective: the present work was aimed to evaluate the effect of different administration modes of sodium valproate(VPA) on bone strength, bone mass and bone mineral density in ovariectomized(OVX) rats and further investigation of the possible mechanism.Methods: 60 female SD rats were randomly divided into 4 groups: Sham group (Sham, n=15), OVX group (OVX, n=15), OVX rats received intermittent VPA treatment group(IVPA, n=15) and OVX rats received daily VPA treatment group(EVPA, n=15). After 12 weeks of treatment, the rats were sacri ced, and serum and femur samples were harvested. DEXA, Micro-CT, histology, biomechanical testing, biochemical index and western blot analysis were used to observe the therapeutic effect and explore the possible mechanism.Results: Micro-CT and DEXA analysis of bones revealed better BMD and higher BV/TV, Tb.Th, Tb.N, Conn. D and lower Tb.Sp at femoral metaphysis with evaluated in IVPA when compared with OVX and EVPA group(P 0.05). Histological, uorescent analysis and biological strength revealed more trabecular bone and higher relative mineral apposition rate, maximal load, elastic modulus and energy at break with evaluated in IVPA when compared with OVX and EVPA group(P 0.05). The levels of P1NP, estrogen, CTX, TRAP5b and RANKL of IVPA group showed a signi cant increase when compared with the OVX and EVPA group(P 0.05). We con rm adverse effects on protein expressions including Notch1, Jagged1, HEY1, Wnt 1, β-catenin and RUNX2 following daily VPA treatment in OVX female rats.Conclusions: Our current study demonstrated that intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats and these effects may be achieved by activating Notch/Wnt/β-catenin/ RUNX2 signal axis.

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Rapamycin could increase the effects of melatonin against age-dependent bone loss

Cited by 12 publications

References 34 publications

Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling

Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling

Melatonin Inhibits Osteoclastogenesis and Osteolytic Bone Metastasis: Implications for Osteoporosis

Intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats

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