TXNIP contributes to bone loss via promoting the mitochondrial oxidative phosphorylation during glucocorticoid-induced osteoporosis

Mo, Yulin; Lai, Wenxiu; Zhong, Ying; Hu, Zhuoqing; You, Meigui; Du, Minqun; Wang, Pan; Wu, Xinyou; Chen, Cailing; He, Huanmin; Gao, Zhimin; Xu, Yang; Wang, Dongtao; Cui, Liao; Yang, Yajun

doi:10.1016/j.lfs.2020.118938

Cited by 17 publications

(14 citation statements)

References 31 publications

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“…Inevitably, the reduction in osteoblastic lineage cells leads to a corresponding reduction in both bone resorption and formation during long-term administration of GC, so-called low bone turnover ( Chotiyarnwong and McCloskey, 2020 ). In this study, a high level of bone turnover was found in the GIO rats, indicating that bone resorption is higher than bone formation, and bone turnover in our study was still in the initial phase of GIO, according to the most commonly situation occurred in our previous studies and other reports ( Cui et al, 2009 ; Cui et al, 2012 ; Yang et al, 2018 ; Zhang et al, 2018 ; Mo et al, 2021 ). Encouragingly, we found that tanshinol at least partially blocked the pathological progression of GIO, even some parameters related to bone metabolism in the Tan group restored to the similar extent like those in the Con group.…”

Section: Discussionsupporting

confidence: 70%

“…Recently, it was found that TXNIP gene highly expressed in the patients with endogenous Cushing’s Syndrome ( Lekva et al, 2012 ). Our previous evidence further revealed that TXNIP elicited bone loss by promoting the excessive mitochondrial oxidative phosphorylation under conditions of oxidative stress induced by GC, which can be blocked in the TXNIP knockout mice ( Mo et al, 2021 ). Several preclinical and clinical evidence related to diabetes mellitus supported the TXNIP-specific inhibitors for the development of new promising agents ( Qayyum et al, 2021 ), such as Verapamil ( Khodneva et al, 2016 ), Taurine ( Gondo et al, 2012 ), and SRI-37330 ( Thielen et al, 2020 ).…”

Section: Discussionmentioning

confidence: 79%

“…Further results indicated that TXNIP modulated osteoblast-mediated osteoclastogenesis by regulating the OPG/RANKL ratio to facilitate bone resorption ( Lekva et al, 2012 ). Hence, limiting TXNIP directly or indirectly may be helpful to ameliorate osteoporosis ( Mo et al, 2021 ; Yang et al, 2021 ). It was reported that high glucose-mediated overexpression of TXNIP induced a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production ( Dunn et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Tanshinol Alleviates Microcirculation Disturbance and Impaired Bone Formation by Attenuating TXNIP Signaling in GIO Rats

Lai

Wang

et al. 2021

Front. Pharmacol.

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Impaired bone formation is the main characteristics of glucocorticoid (GC)-induced osteoporosis (GIO), which can be ameliorated by tanshinol, an aqueous polyphenol isolated from Salvia miltiorrhiza Bunge. However, the underlying mechanism is still not entirely clear. In the present study, we determined the parameters related to microstructure and function of bone tissue, bone microcirculation, and TXNIP signaling to investigate the beneficial effects of tanshinol on skeleton and its molecular mechanism in GIO rats. Male Sprague-Dawley rats aged 4 months were administrated orally with distilled water (Con), tanshinol (Tan, 25 mg kg−1 d−1), prednisone (GC, 5 mg kg−1 d−1) and GC plus tanshinol (GC + Tan) for 14 weeks. The results demonstrated that tanshinol played a significant preventive role in bone loss, impaired microstructure, dysfunction of bone metabolism and poor bone quality, based on analysis of correlative parameters acquired from the measurement by using Micro-CT, histomorphometry, ELISA and biomechanical assay. Tanshinol also showed a significant protective effect in bone microcirculation according to the evidence of microvascular perfusion imaging of cancellous bone in GIO rats, as well as the migration ability of human endothelial cells (EA.hy926, EA cells). Moreover, tanshinol also attenuated GC-elicited the activation of TXNIP signaling pathway, and simultaneously reversed the down-regulation of Wnt and VEGF pathway as manifested by using Western-blot method in GIO rats, EA cells, and human osteoblast-like MG63 cells (MG cells). Collectively, our data highlighted that tanshinol ameliorated poor bone health mediated by activation of TXNIP signaling via inhibiting microcirculation disturbance and the following impaired bone formation in GIO rats.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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Tanshinol Alleviates Microcirculation Disturbance and Impaired Bone Formation by Attenuating TXNIP Signaling in GIO Rats

Lai

Wang

et al. 2021

Front. Pharmacol.

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“…Osteoporosis (OP) is a chronic, systemic endocrine and metabolic disorder, whether it is primary osteoporosis due to aging or sex hormone deficiency or secondary osteoporosis due to hyperthyroidism, diabetes, obesity, Cushing's syndrome, anorexia, rheumatoid arthritis and drug effects. The underlying mechanism is the imbalance of bone remodeling in which the loss of bone mass occurs faster than bone production (5)(6)(7)(8)(9)(10)(11). Osteoporosis and related fractures have become a major public health problem and have substantially increased health care costs.…”

Section: Introductionmentioning

confidence: 99%

The Role of Osteoclast Energy Metabolism in the Occurrence and Development of Osteoporosis

Lin

Zhu

2021

Front. Endocrinol.

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In recent decades, the mechanism underlying bone metabolic disorders based on energy metabolism has been heavily researched. Bone resorption by osteoclasts plays an important role in the occurrence and development of osteoporosis. However, the mechanism underlying the osteoclast energy metabolism disorder that interferes with bone homeostasis has not been determined. Bone resorption by osteoclasts is a process that consumes large amounts of adenosine triphosphate (ATP) produced by glycolysis and oxidative phosphorylation. In addition to glucose, fatty acids and amino acids can also be used as substrates to produce energy through oxidative phosphorylation. In this review, we summarize and analyze the energy-based phenotypic changes, epigenetic regulation, and coupling with systemic energy metabolism of osteoclasts during the development and progression of osteoporosis. At the same time, we propose a hypothesis, the compensatory recovery mechanism (involving the balance between osteoclast survival and functional activation), which may provide a new approach for the treatment of osteoporosis.

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“…have found that high concentrations of GC can induce oxidative stress and BMSC death [40]. Several studies have also indicated that oxidative stress is a contributing factor to the pathological process of SIOP, and TXNIP protein can reduce oxidative stress and reverse the process of bone loss by upregulating the MOP pathway [41]. Ferroptosis is caused by the inhibition of GPX4 and system xc -, which leads to cystine metabolism inhibition, enhanced lipid peroxidation, and iron metabolism dysfunction, and generates a large amount of ROS and triggers cell death [11].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Inhibits the Ferroptotic Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K-AKT-mTOR Signaling Axis to Attenuate Steroid-induced Osteoporosis

Li¹,

Yang²,

Li³

et al. 2021

Preprint

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ObjectivesSteroid-induced osteoporosis (SIOP) is a secondary osteoporosis, which is a systemic bone disease characterized by low bone mass, bone microstructure damage, increased bone fragility, and easy fracture. However, the specific mechanism remains unclear. Glucocorticoid-induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron-dependent programmed cell death that differs from apoptosis, cell necrosis, and autophagy, which can be induced by many factors. Herein, we aimed to explore whether glucocorticoids (GCs) cause ferroptosis in BMSCs and determine possible treatment pathways and mechanisms of action. Melatonin (MT), a hormone secreted by the pineal gland, displays strong antioxidant abilities to scavenge free radicals and alleviates ferroptosis in many tissues and organs. MethodsIn this study, we used high-dose dexamethasone (DEX) to observe whether glucocorticoids induced ferroptosis in BMSCs. We then assessed whether MT can inhibit the ferroptotic pathway, thereby providing early protection against GC-induced SIOP, and investigated the signaling pathways involved.ResultsIn vitro experiments showed that MT intervention significantly improved GC-induced ferroptosis in BMSCs and significantly improved SIOP in vivo. Pathway analysis showed that MT improves ferroptosis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the anti-ferroptosis effect of MT, but after blocking the PI3K pathway, the effect of MT is weakened. Obviously, MT can protect against SIOP induced by GC. Notably, even after GC-induced ferroptosis begins, MT can confer protection against SIOP. ConclusionOur research confirms that GC-induced ferroptosis is closely related to SIOP. Melatonin can inhibit ferroptosis by activating the PI3K-AKT-mTOR signaling pathway, thereby reducing the occurrence of steroid-induced osteoporosis. Therefore, MT may provide a novel strategy for preventing and treating SIOP.

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TXNIP contributes to bone loss via promoting the mitochondrial oxidative phosphorylation during glucocorticoid-induced osteoporosis

Cited by 17 publications

References 31 publications

Tanshinol Alleviates Microcirculation Disturbance and Impaired Bone Formation by Attenuating TXNIP Signaling in GIO Rats

Tanshinol Alleviates Microcirculation Disturbance and Impaired Bone Formation by Attenuating TXNIP Signaling in GIO Rats

The Role of Osteoclast Energy Metabolism in the Occurrence and Development of Osteoporosis

Melatonin Inhibits the Ferroptotic Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K-AKT-mTOR Signaling Axis to Attenuate Steroid-induced Osteoporosis

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