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

Abstract

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.

Picein alleviates oxidative stress and promotes bone regeneration in osteoporotic bone defect by inhibiting ferroptosis via Nrf2/HO‐1/GPX4 pathway

“…Nowadays, osteoporotic fracture has become a global health problem, leading to a significant reduction in quality of life and huge socio‐economic burden 25 . Bone homeostasis is a complex sequence of bone resorption and bone formation and integrity of bone tissue are maintained by various factors such as BMSCs, 26 osteoclasts and osteoblasts, 27 macrophages, 3 blood vessels, 28 or calcium ions 29 . Oxidative stress can cause potentially harmful effects on cells, such as protein oxidation or oxidative DNA damage, which are considered crucial reasons in triggering various pathologic changes related to tissue injury, 30 including OP 4 .…”

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future

“…The decline in estrogen level can accelerate bone loss and increase the risk of developing osteoporosis. This commonly occurs in postmenopausal women and patients who have undergone surgical removal of their ovaries ( E et al, 2016 ; Qi et al, 2023 ).…”

“…The decline in estrogen level can accelerate bone loss and increase the risk of developing osteoporosis. This commonly occurs in postmenopausal women and patients who have undergone surgical removal of their ovaries (E et al, 2016;Qi et al, 2023). ERα in human osteoblasts can exert osteogenic effects through the CSE/H2S signaling pathway and modulation of NF-κB activity (Lambertini et al, 2017), and suppress bone cell apoptosis.…”

Therapeutic potential of mesenchymal stem cell-derived exosomes in skeletal diseases

“…Their ability to sustain bone homeostasis declines with aging, menopause, and ovariectomy (OVX), resulting in the accumulation of bone mineral adipocytes, ultimately leading to OP ( Behera and Tyagi, 2018 ; Zeng and Xie, 2022 ; Ding et al, 2023 ). OVX-induced OP ( Luo et al, 2019 ; Yahao and Xinjia, 2021 ; Cui et al, 2022 ; Qi et al, 2023 ), senile OP (SOP) ( Lu et al, 2020 ), disuse OP (DOP) ( Yang et al, 2020 ), glucocorticoid-induced OP (GIOP) ( Yao et al, 2023 ), and diabetic OP ( Zhang et al, 2021 ) are the models typically used to assess the therapeutic effect of MSC-exosomes in OP ( Table 2 ). Bone marrow-derived MSCs are usually used to generate exosomes ( Luo et al, 2019 ; Lu et al, 2020 ; Li et al, 2021 ; Qi et al, 2023 ), as are hucMSCs ( Yang et al, 2020 ), ADSCs ( Yao et al, 2023 ), and induced pluripotent stem cells (iPSCs) ( Cui et al, 2022 ).…”

“…OVX-induced OP ( Luo et al, 2019 ; Yahao and Xinjia, 2021 ; Cui et al, 2022 ; Qi et al, 2023 ), senile OP (SOP) ( Lu et al, 2020 ), disuse OP (DOP) ( Yang et al, 2020 ), glucocorticoid-induced OP (GIOP) ( Yao et al, 2023 ), and diabetic OP ( Zhang et al, 2021 ) are the models typically used to assess the therapeutic effect of MSC-exosomes in OP ( Table 2 ). Bone marrow-derived MSCs are usually used to generate exosomes ( Luo et al, 2019 ; Lu et al, 2020 ; Li et al, 2021 ; Qi et al, 2023 ), as are hucMSCs ( Yang et al, 2020 ), ADSCs ( Yao et al, 2023 ), and induced pluripotent stem cells (iPSCs) ( Cui et al, 2022 ). The effects of MSC-exosomes in OP is mediated by enhancement of osteogenesis and angiogenesis, possibly via the vasohibin 1 (VASH1) ( Lu et al, 2020 ), Mob1/Hippo ( Yang et al, 2020 ), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) ( Zhang et al, 2021 ), schnurri-3 (Shn3)/Slit guidance ligand 3 (SLIT3) ( Cui et al, 2022 ), and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO1) ( Yao et al, 2023 ) signaling pathways ( Figure 4 ).…”