AKT/GSK3β/NFATc1 and ROS signal axes are involved in AZD1390-mediated inhibitory effects on osteoclast and OVX-induced osteoporosis

Yang, Shuyue; Song, Dezhi; Wang, Ziyi; Su, Yuangang; Chen, Junchun; Xian, Yansi; Huang, Jian; Li, Jing; Xu, Jiake; Zhao, Jinmin; Liu, Qian

doi:10.1016/j.intimp.2022.109370

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…The persistent production of c-Fos is supported by the phosphorylation of ERK, which in turn stimulates NFATc1 in osteoclast progenitors and ultimately results in osteoclastogenesis (45). According to previous research, AKT promoted the formation of the inactive form of GSK3β (p-GSK3β), as well as the nuclear localization of NFATc1, whereas constitutively active GSK3β overexpression inhibited osteoclast formation by downregulating NFATc1 (46)(47)(48). The results of the present study demonstrated that cas inhibited the phosphorylation of AKT/GSK3β and thus prevented the expression of related proteins and transcription factors required for osteoclast maturation, as well as the expression of the osteoclast-associated genes, Nfatc1, Fos, Atp6v0d2, Ctsk, Dcstamp, and Mmp9 (Fig.…”

Section: Discussionmentioning

confidence: 96%

Casticin suppresses RANKL‑induced osteoclastogenesis and prevents ovariectomy‑induced bone loss by regulating the AKT/ERK and NF‑κB signaling pathways

Yang

Liang

et al. 2023

Int J Mol Med

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Postmenopausal osteoporosis is a systemic metabolic disease that chronically endangers public health and is typically characterized by low bone mineral density and marked bone fragility. The excessive bone resorption activity of osteoclasts is a major factor in the pathogenesis of osteoporosis; therefore, strategies aimed at inhibiting osteoclast activity may prevent bone decline and attenuate the process of osteoporosis. casticin (cas), a natural compound, has anti-inflammatory and antitumor properties. However, the role of cas in bone metabolism remains largely unclear. The present study found that the receptor activator of nuclear factor-κΒ (NF-κB) ligand-induced osteoclast activation and differentiation were inhibited by cas. Tartrate-resistant acid phosphatase staining revealed that cas inhibited osteoclast differentiation, and bone resorption pit assays demonstrated that Cas affected the function of osteoclasts. Cas significantly reduced the expression of osteoclast-specific genes and related proteins, such as nuclear factor of activated T cells, cytoplasmic 1 and c-Fos at the mRNA and protein level in a concentration-dependent manner. cas inhibited osteoclast formation by blocking the AKT/ERK and NF-κB signaling pathways, according to the intracellular signaling analysis. The microcomputed tomography and tissue staining of tibiae from ovariectomized mice revealed that cas prevented the bone loss induced by estrogen deficiency and reduced osteoclast activity in vivo. Collectively, these findings indicated that Cas may be used to prevent osteoporosis.

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Section: Discussionmentioning

confidence: 96%

Casticin suppresses RANKL‑induced osteoclastogenesis and prevents ovariectomy‑induced bone loss by regulating the AKT/ERK and NF‑κB signaling pathways

Yang

Liang

et al. 2023

Int J Mol Med

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“…In vitro, AZD1390 halted osteoclastogenesis by suppressing the PI3K/AKT signalling cascade. Protein expression of p-AKT and p-GSK3β were decreased after treatment with AZD1390 [9]. PDK1 serves as the downstream effector of the PI3K essential for AKT phosphorylation.…”

Section: Pi3k/akt Signalling Pathwaymentioning

confidence: 98%

“…AZD1390 is a brain penetrant ataxia telangiectasia mutant (ATM) kinase inhibitor that blocks ATM-dependent signalling and repair of deoxyribonucleic acid (DNA) double-strand breaks. For parameters related to osteoclastogenesis, treatment of AZD1390 reduced Oc.N and cathepsin K (CTSK) expression level in the ovariectomised mice [9]. Oral administration of imperatorin reduced TRAP staining indicating low osteoclast activity in the ovariectomised rats [10].…”

Section: In Vivo Evidence On the Role Of Gsk3β On Bone Resorptionmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Beta (GSK3β) as a Potential Drug Target in Regulating Osteoclastogenesis: An Updated Review on Current Evidence

Wong

2024

Biomolecules

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Glycogen synthase kinase 3-beta (GSK3β) is a highly conserved protein kinase originally involved in glucose metabolism, insulin activity, and energy homeostasis. Recent scientific evidence demonstrated the significant role of GSK3β in regulating bone remodelling through involvement in multiple signalling networks. Specifically, the inhibition of GSK3β enhances the conversion of osteoclast progenitors into mature osteoclasts. GSK3β is recognised as a pivotal regulator for the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), nuclear factor-kappa B (NF-κB), nuclear factor-erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1), canonical Wnt/beta (β)-catenin, and protein kinase C (PKC) signalling pathways during osteoclastogenesis. Conversely, the inhibition of GSK3β has been shown to prevent bone loss in animal models with complex physiology, suggesting that the role of GSK3β may be more significant in bone formation than bone resorption. Divergent findings have been reported regarding the efficacy of GSK3β inhibitors as bone-protecting agents. Some studies demonstrated that GSK3β inhibitors reduced osteoclast formation, while one study indicated an increase in osteoclast formation in RANKL-stimulated bone marrow macrophages (BMMs). Given the discrepancies observed in the accumulated evidence, further research is warranted, particularly regarding the use of GSK3β silencing or overexpression models. Such efforts will provide valuable insights into the direct impact of GSK3β on osteoclastogenesis and bone resorption.

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“…[18][19][20][21] PI3K/AKT inhibitors, such as Alpinetin, AZD1390, etc., have been reported to alleviate osteoclast-associated bone metabolic disorders by inhibiting osteoclast differentiation. 22,23 However, the effect of AS on osteoclast-related bone loss is unclear. Therefore, this study aimed to determine the influence of AS on the differentiation and functions of osteoclasts in the presence of RANKL.…”

Section: Introductionmentioning

confidence: 99%

AS-605240 Blunts Osteoporosis by Inhibition of Bone Resorption

Sun¹,

Cai²,

Shen³

et al. 2023

DDDT

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Background: Osteoporosis is a metabolic bone disease. Osteoclasts are significantly involved in the pathogenesis of osteoporosis. AS-605240 (AS) is a small molecule PI3K-γ inhibitor and is less toxic compared to pan-PI3K inhibitors. AS also exerts multiple biological effects including anti-inflammatory, anti-tumor, and myocardial remodeling promotion. However, the involvement of AS in the differentiation and functions of osteoclasts and the effect of AS in treating patients with osteoporosis is still unclear.Purpose: This study aimed to investigate if AS inhibits the differentiation of osteoclasts and resorption of the bones induced by M-CSF and RANKL. Next, we evaluated the therapeutic effects of AS on bone loss in ovariectomy (OVX)-induced osteoporosis mice models. Methods: We stimulated bone marrow-derived macrophages with an osteoclast differentiation medium containing different AS concentrations for 6 days or 5μM AS at different times. Next, we performed tartrate-resistant acid phosphatase (TRAP) staining, bone resorption assay, F-actin ring fluorescence, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting (WB). Next, MC3T3-E1s (pre-osteoblast cells) were differentiated to osteoblast by stimulating the cells with varying AS concentrations. Next, we performed alkaline phosphatase (ALP) staining, RT-qPCR, and WB on these cells. We established an OVX-induced osteoporosis mice model and treated the mice with 20mg/kg of AS. Finally, we extracted the femurs and performed micro-CT scanning, H&E, and TRAP staining. Results: AS inhibits the formation of osteoclasts and resorption of bone triggered by RANKL by inhibiting the PI3K/Akt signaling pathway. Furthermore, AS enhances the differentiation of osteoblasts and inhibits bone loss due to OVX in vivo. Conclusion: AS inhibits osteoclast production and enhances osteoblast differentiation in mice, thus providing a new therapeutic approach for treating patients with osteoporosis.

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AKT/GSK3β/NFATc1 and ROS signal axes are involved in AZD1390-mediated inhibitory effects on osteoclast and OVX-induced osteoporosis

Cited by 8 publications

References 42 publications

Casticin suppresses RANKL‑induced osteoclastogenesis and prevents ovariectomy‑induced bone loss by regulating the AKT/ERK and NF‑κB signaling pathways

Casticin suppresses RANKL‑induced osteoclastogenesis and prevents ovariectomy‑induced bone loss by regulating the AKT/ERK and NF‑κB signaling pathways

Glycogen Synthase Kinase-3 Beta (GSK3β) as a Potential Drug Target in Regulating Osteoclastogenesis: An Updated Review on Current Evidence

AS-605240 Blunts Osteoporosis by Inhibition of Bone Resorption

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