Melatonin increases bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats via the promotion of osteogenesis

Guan, Huanshuai; Kong, Ning; Tian, Run; Cao, Ruomu; Liu, Guanzhi; Li, Yiyang; Wei, Qilu; Jiao, Ming; Lei, Yutian; Xing, Fangze; Tian, Peng; Wang, Kunzheng; Yang, Pei

doi:10.1186/s12967-022-03341-7

Cited by 23 publications

(14 citation statements)

References 35 publications

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“…The size distribution of most exosomes ranged from 50 to 120 nm (Fig. 2 C), which was consistent with other reports [ 15 , 28 ]. The data indicated that the microvesicles derived from BMSCs were successfully obtained, and were predominantly exosomes.…”

Section: Resultssupporting

confidence: 92%

ERK-estrogen receptor α signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss

Shen²,

Shu

et al. 2023

J Orthop Surg Res

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Background Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) are considered as candidates for osteoporosis (OP) therapy. Estrogen is critical in the maintenance of bone homeostasis. However, the role of estrogen and/or its receptor in BMSC-Exos treatment of OP, as well as its methods of regulation during this process remain unclear. Methods BMSCs were cultured and characterized. Ultracentrifugation was performed to collect BMSC-Exos. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to identify BMSC-Exos. We examined the effects of BMSC-Exos on the proliferation, osteogenic differentiation, mineralization, and cell cycle distribution of MG-63 cells. The protein expression of estrogen receptor α (ERα) and the phosphorylation of ERK were investigated through western blotting. We determined the effects of BMSC-Exos on the prevention of bone loss in female rats. The female Sprague–Dawley rats were divided into three groups: the sham group, ovariectomized (OVX) group, and the OVX + BMSC-Exos group. Bilateral ovariectomy was performed in the OVX and OVX + BMSC-Exos groups, while a similar volume of adipose tissue around the ovary was removed in the sham group. The rats in OVX group and OVX + BMSC-Exos group were given PBS or BMSC-Exos after 2 weeks of surgery. Micro-CT scanning and histological staining were used to evaluate the in vivo effects of BMSC-Exos. Results BMSC-Exos significantly enhanced the proliferation, alkaline phosphatase activity, and the Alizarin red S staining in MG-63 cells. The results of cell cycle distribution demonstrated that BMSC-Exos increased the proportion of cells in the G2 + S phase and decreased the proportion of cells in the G1 phase. Moreover, PD98059, an inhibitor of ERK, inhibited both the activation of ERK and the expression of ERα, which were promoted by administration of BMSC-Exos. Micro-CT scan showed that in the OVX + BMSC-Exos group, bone mineral density, bone volume/tissue volume fraction, trabecular number were significantly upregulated. Additionally, the microstructure of the trabecular bone was preserved in the OVX + BMSC-Exos group compared to that in the OVX group. Conclusion BMSC-Exos showed an osteogenic-promoting effect both in vitro and in vivo, in which ERK-ERα signaling might play an important role.

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Section: Resultssupporting

confidence: 92%

ERK-estrogen receptor α signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss

Shen²,

Shu

et al. 2023

J Orthop Surg Res

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“…The size distribution of most exosomes ranged from 50 nm to 120 nm (Fig. 2C), which was consistent with other reports [14,23]. The data indicated that the microvesicles derived from BMSCs were successfully obtained, and were predominantly exosomes.…”

Section: Characterization Of Bmscs and Bmscs-exossupporting

confidence: 91%

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Protect Bone against Ovariectomy‑Induced Osteoporosis through ERK Signaling by Estrogen Receptor α

Qi¹,

Shen

et al. 2022

Preprint

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Background: Exosomes derived from bone marrow stem cells (BMSC-Exos) are considered as candidates for osteoporosis (OP) therapy. Estrogen is critical in the maintenance of bone homeostasis. However, the role of estrogen and/or its receptor in BMSC-Exos treatment of OP, as well as its methods of regulation during this process remain unclear.Methods: BMSCs were cultured and characterized. Ultracentrifugation was performed to collect BMSC-Exos. Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting were used to identify BMSC-Exos. We examined the effects of BMSC-Exos on the proliferation, osteogenic differentiation, mineralization, and cell cycle distribution of MG-63 cells. The protein expression of estrogen receptor α (ERα) and the phosphorylation of extracellular signal-regulated kinase (ERK) were investigated through western blotting. We determined the effects of BMSC-Exos on the prevention of bone loss in female rats. The female SD rats were divided into three groups: the sham group, ovariectomized (OVX) group, and the OVX + BMSC-Exos group. Bilateral ovariectomy was performed in the OVX and OVX + BMSC-Exos groups, while a similar volume of adipose tissue around the ovary was removed in the sham group. The rats in OVX+BMSC-Exos group were given BMSC-Exos after 2 weeks of surgery. Micro-CT scanning and histological staining were used to evaluate the in vivo effects of BMSC-Exos.Results: BMSC-Exos significantly upregulated the proliferation, ALP activity, and the ARS staining in MG-63 cells. The results of cell cycle distribution demonstrated that BMSC-Exos significantly increased the proportion of cells in the G2+S phase and decreased the proportion of cells in the G1 phase. Moreover, PD98059, an inhibitor of ERK, downregulated the expression of ERα, which was promoted by administration of BMSC-Exos. Micro-CT scan showed that in the OVX+BMSC-Exos group, BMSC-Exos significantly promoted ERα expression, with ameliorated bone mineral density (BMD), bone volume/tissue volume fraction (BV/TV), trabecular number (Tb. N), and trabecular separation (Tb. Sp). Additionally, the microstructure of the trabecular bone was preserved in the OVX + BMSC-Exos group compared to that in the OVX group.Conclusion: BMSC-Exos showed an anti-osteoporotic role in OVX rats both in vitro and in vivo, which may involve the ERα/ERK signaling pathway.

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“…Kobayashi-Sun et al [138] reported that melatonin inhibits the differentiation of both osteoblasts and osteoclasts in the zebrafish scale because it prevents the Erk signaling cascade. These results contrast with those obtained in the in vitro model of mammalian cells, and also in vivo in which melatonin increases bone formation [139]. This negative effect of melatonin on osteoblasts has also been seen when incubated with osteoclasts [140].…”

Section: Regulation Of Bone Metabolism By Melatonin In Zebrafishcontrasting

confidence: 90%

The Zebrafish, an Outstanding Model for Biomedical Research in the Field of Melatonin and Human Diseases

Aranda-Martínez

Fernández‐Martínez

Ramírez-Casas

et al. 2022

IJMS

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The zebrafish has become an excellent model for the study of human diseases because it offers many advantages over other vertebrate animal models. The pineal gland, as well as the biological clock and circadian rhythms, are highly conserved in zebrafish, and melatonin is produced in the pineal gland and in most organs and tissues of the body. Zebrafish have several copies of the clock genes and of aanat and asmt genes, the latter involved in melatonin synthesis. As in mammals, melatonin can act through its membrane receptors, as with zebrafish, and through mechanisms that are independent of receptors. Pineal melatonin regulates peripheral clocks and the circadian rhythms of the body, such as the sleep/wake rhythm, among others. Extrapineal melatonin functions include antioxidant activity, inducing the endogenous antioxidants enzymes, scavenging activity, removing free radicals, anti-inflammatory activity through the regulation of the NF-κB/NLRP3 inflammasome pathway, and a homeostatic role in mitochondria. In this review, we introduce the utility of zebrafish to analyze the mechanisms of action of melatonin. The data here presented showed that the zebrafish is a useful model to study human diseases and that melatonin exerts beneficial effects on many pathophysiological processes involved in these diseases.

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Melatonin increases bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats via the promotion of osteogenesis

Cited by 23 publications

References 35 publications

ERK-estrogen receptor α signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss

ERK-estrogen receptor α signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Protect Bone against Ovariectomy‑Induced Osteoporosis through ERK Signaling by Estrogen Receptor α

The Zebrafish, an Outstanding Model for Biomedical Research in the Field of Melatonin and Human Diseases

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