Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway

Zhang, Yun; Yan, Ming; Kuang, Shumeng; Lou, Yiqiang; Wu, Shouqian; Li, Yurong; Wang, Zihan; Mao, Hong-Jiao

doi:10.1016/j.ecoenv.2021.113119

Cited by 16 publications

(17 citation statements)

References 54 publications

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“…These data suggest that estrogen deficiency can lead to an increase in oxidative stress levels in vivo , which in turn triggers its downstream protective autophagic response, but ultimately leads to the development of osteoporosis due to its limited protective effect. Further exploration of the negative feedback protection mechanism of autophagy in osteocytes has revealed that ROS/MAPK/ERK and ROS/mTOR/ULK1 signaling axes appear to play important roles ( 97 , 98 ).…”

Section: Regulation Of Autophagy In Oxidative Stressmentioning

confidence: 99%

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Autophagy in Bone Remodeling: A Regulator of Oxidative Stress

et al. 2022

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Bone homeostasis involves bone formation and bone resorption, which are processes that maintain skeletal health. Oxidative stress is an independent risk factor, causing the dysfunction of bone homeostasis including osteoblast-induced osteogenesis and osteoclast-induced osteoclastogenesis, thereby leading to bone-related diseases, especially osteoporosis. Autophagy is the main cellular stress response system for the limination of damaged organelles and proteins, and it plays a critical role in the differentiation, apoptosis, and survival of bone cells, including bone marrow stem cells (BMSCs), osteoblasts, osteoclasts, and osteocytes. High evels of reactive oxygen species (ROS) induced by oxidative stress induce autophagy to protect against cell damage or even apoptosis. Additionally, pathways such as ROS/FOXO3, ROS/AMPK, ROS/Akt/mTOR, and ROS/JNK/c-Jun are involved in the regulation of oxidative stress-induced autophagy in bone cells, including osteoblasts, osteocytes and osteoclasts. This review discusses how autophagy regulates bone formation and bone resorption following oxidative stress and summarizes the potential protective mechanisms exerted by autophagy, thereby providing new insights regarding bone remodeling and potential therapeutic targets for osteoporosis.

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Section: Regulation Of Autophagy In Oxidative Stressmentioning

confidence: 99%

“…Furthermore, NAC treatment attenuated the level of ROS-mediated autophagy. This suggests that the high level of ROS caused by BPA acts upstream of the mTOR/ULK1 signaling axis and that the autophagic response that it triggers is protective against the cytotoxic effects of BPA ( 98 ).…”

Section: Regulation Of Autophagy In Oxidative Stressmentioning

confidence: 99%

Autophagy in Bone Remodeling: A Regulator of Oxidative Stress

et al. 2022

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“…Several studies have shown that mTOR signaling is involved in the activation of autophagy in chondrocytes in OA [ 36 , 39 , 40 ]. Inhibition of the activity of mTOR improves autophagy by directly phosphorylating the serine sites of ULK1, an important regulatory protein for autophagy induction [ 41 ]. This inhibition effectively elevates autophagic flux, including the levels of Beclin1 and LC3 II.…”

Section: Discussionmentioning

confidence: 99%

tRNA-Derived Fragment tRF-5009A Regulates Autophagy and Degeneration of Cartilage in Osteoarthritis via Targeting mTOR

Deng

Long

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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tRNA-derived fragments (tRFs) have been reported to have critical regulatory roles in osteoarthritis (OA). Recent studies have suggested that autophagy promotes the homeostasis of the extracellular matrix of chondrocytes in OA. However, the role of tRFs in posttranscriptional gene regulation during autophagy in OA is unknown. Therefore, we explored the role of tRF-5009A in the posttranscriptional gene regulation of autophagy and cartilage degeneration in OA. Using RNA sequencing, we identified tRF-5009A, the tRNAValCAC-derived fragment, in OA tissues and explored its expression by quantitative reverse transcription PCR and fluorescence in situ hybridization. We further investigated the relationship between the expression of tRF-5009A and clinical factors in OA. Chondrocytes were transfected with a tRF-5009A inhibitor or mimic to determine their functions, including in relation to autophagy and the cartilage phenotype. A rescue experiment and dual-luciferase reporter assay were conducted to determine whether the 3 ′ -untranslated region (UTR) of mTOR contains a tRF-5009A-binding site. tRF-5009A was downregulated in the cartilage of OA knees, especially in damaged areas. mTOR was highly expressed in damaged cartilage and negatively correlated with the expression of tRF-5009A; transfection with a tRF-5009A inhibitor promoted the expression of mTOR and suppressed autophagy, whereas transfection with a tRF-5009A mimic had the opposite effect. A dual-luciferase reporter assay showed that tRF-5009A silenced the expression of mTOR by binding to its 3 ′ -UTR. Thus, tRF-5009A regulates autophagy and cartilage degeneration in OA by targeting mTOR. In summary, these findings provide an additional tool for the clinical diagnosis and novel targeted therapy of OA.

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“…P1NP levels were expected to increase, reflecting increased bone formation with growth, whereas CTX-I levels indicate a bone resorption process [ 42 ]. After BPA exposure, stimulated proliferation and collagen accumulation could be expected in osteoblasts but not in osteoclasts [ 17 ], whereas negative effects such as apoptosis, pyroptotic death, and autophagy were induced in osteocytes [ 40 , 41 ]. Even when we tried to eliminate or control most of the possible disrupting factors (diet, age, sex, breed, housing, season, circadian rhythm, climate, time of blood collection, location and storage, methodology, prior validation) [ 46 ], their variability was significant.…”

Section: Discussionmentioning

confidence: 99%

“…Kim et al demonstrated that BPA and its alternatives, bisphenol F and tetramethyl bisphenol F (TMBPF), are not toxic to osteoclast differentiation in vitro; in fact, TMBPF enhanced this process [ 39 ]. Recent studies on BPA also reported its effects on osteocytes (inhibited cell viability, apoptosis, and pyroptotic death) that potentially adversely contribute to the development and metabolism of bone [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Experimental Exposure to Bisphenol A Has Minimal Effects on Bone Tissue in Growing Rams—A Preliminary Study

Brankovič

Leskovec

Šturm

et al. 2022

Animals

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Bisphenol A (BPA) is a well-known synthetic compound that belongs to the group of endocrine-disrupting chemicals. Although bone tissue is a target for these compounds, studies on BPA-related effects on bone morphology in farm animals are limited. In this preliminary study, we investigated the effects of short-term dietary BPA exposure on femoral morphology, metabolism, mineral content, and biomechanical behavior in rams aged 9–12 months. Fourteen rams of the Istrian Pramenka breed were randomly divided into a BPA group and a control group (seven rams/group) and exposed to 25 µg BPA/kg bw for 64 days in feed. Blood was collected for determination of bone turnover markers (procollagen N-terminal propeptide, C-terminal telopeptide), and femurs were assessed via computed tomography, histomorphometry, three-point bending test, and mineral analysis. BPA had no significant effects on most of the parameters studied. Only mineral analysis showed decreased manganese (50%; p ≤ 0.05) and increased copper content (25%; p ≤ 0.05) in the femurs of BPA-exposed rams. These results suggest that a 2-month, low-dose exposure to BPA in growing rams did not affect the histomorphology, metabolism, and biomechanical behavior of femurs; however, it affected the composition of microelements, which could affect the histometric and biophysical properties of bone in the long term.

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Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway

Cited by 16 publications

References 54 publications

Autophagy in Bone Remodeling: A Regulator of Oxidative Stress

Autophagy in Bone Remodeling: A Regulator of Oxidative Stress

tRNA-Derived Fragment tRF-5009A Regulates Autophagy and Degeneration of Cartilage in Osteoarthritis via Targeting mTOR

Experimental Exposure to Bisphenol A Has Minimal Effects on Bone Tissue in Growing Rams—A Preliminary Study

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