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Relationship: 2846

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Oxidative Stress leads to Altered Bone Cell Homeostasis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leading to occurrence of bone loss non-adjacent Moderate Low Vinita Chauhan (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Low NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male Moderate
Female Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate
Juvenile Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The tight regulation of differentiation pathways leading to bone-forming osteoblasts (osteoblastogenesis) and bone-resorbing osteoclasts (osteoclastogenesis) is essential for the maintenance of osteogenic balance, i.e., the deposition and resorption of bone matrix. As such, perturbations by the overproduction of reactive oxygen species (ROS) during oxidative stress can have devastating effects on the delicate balance of bone cell (i.e., osteocyte, osteoclast, and osteoblast) differentiation and function. 

Oxidative stress disrupts the homeostatic balance of osteoblastic bone deposition and osteoclastic bone resorption by altering the osteoblastogenic/osteoclastogenic differentiation pathways through the overproduction of ROS (Tian et al., 2017). Briefly, ROS produced in pre-osteoblasts and pre-osteoclasts will affect the activities of different signaling molecules in the respective cell types. In osteoblasts, ROS naturally upregulate expression of the transcription factor forkhead box O (FoxO) which enhances cell antioxidant status. FoxO requires ß-catenin binding, which sequesters ß-catenin from the main osteoblast differentiation pathway, the Wnt/ß-catenin pathway, ultimately downregulating osteoblastogenesis and the expression of alkaline phosphatase (ALP) and osteocalcin (OCN) (Manolagas and Almeida, 2007; Tian et al., 2017). Further, ROS upregulate the receptor activator of nuclear factor kappa B ligand (RANK-L), which is the main regulator of osteoclastogenesis. By increasing RANK-L production, ROS inhibits osteoclast apoptosis and promotes osteoclastogenesis and the expression of tartrate-resistant acid phosphatase (TRAP), Cathepsin K (CTSK), and HCl (Tian et al., 2017).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall weight of evidence: Moderate

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological rationale for connection of increased oxidative stress to altered bone cell homeostasis is well-supported by research. Tian et al. (2017) reviewed the influence of oxidative stress on osteoblasts and osteoclasts by the increased production of ROS and its resulting effect on bone resorption and deposition in the space environment. Several other papers evaluated the impact of oxidative stress on osteoclastogenesis and osteoblastogenesis and the crucial role of ROS in up and downregulation of bone resorption and deposition (Bartell et al., 2014; Donaubauer, et al., 2020; Maeda et al., 2019; Manolagas et al., 2007; Tahimic and Globus, 2017).

Increased ROS production during oxidative stress plays crucial and opposing roles in osteoclast and osteoblast differentiation, activation and inhibition, respectively. Cells use FoxO transcription factors to defend against oxidative stress by upregulating production of antioxidant enzymes. In osteoblasts, FoxO-mediated transcription differs between mature osteoblasts and differentiating osteoblasts precursors (Almeida 2011). In mature osteoblasts FoxO directly regulates the transcription of genes involved in cell survival and proliferation (Almeida 2011). During differentiation of osteoblasts precursors FoxO requires binding of ß-catenin before translocating into the nucleus and regulating gene expression (Almeida 2011). ß-catenin is also a well-known component of the Wnt/ß-catenin signaling pathway which is essential to osteoblast differentiation. Thus, increased FoxO production under oxidative stress divert ß-catenin, directly downregulating osteoblast differentiation and deposition of bone matrix (Maeda et al., 2019; Manolagas et al., 2007; Tian et al., 2017).

The opposite effect was found in osteoclasts. Increased ROS production in osteoblasts enhances the production of RANK-L, a ligand for RANK, the main regulator of osteoclast differentiation. Upon RANK-RANK-L interaction, transcription and translation of osteoclast-specific genes involved in bone matrix resorption by nuclear factor of activated T cells 1 (NFATc1), the master transcription factor for osteoclastogenesis, occurs (Donaubauer et al., 2020; Tahimic and Globus, 2017; Tian et al., 2017). Further, RANK-RANKL interaction supresses FoxO transcription in osteoclasts feeding osteoclastogenesis (Bartell et al., 2014). Accumulation of H2O2, the most abundant form of ROS, is pivotal for osteoclastogenesis as it stimulates osteoclast progenitor proliferation and prolongs survival of mature osteoclasts; the enhanced production of RANK-L by ROS feeds into this by suppressing FoxO transcriptional activity, thereby preventing ROS-scavenging by antioxidant enzymes and creating a positive feedback loop for osteoclast stimulation (Bartell et al., 2014).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help
  • One study suggests X-ray radiation results in a dose-dependent increase in oxidative stress and bone resorption parameters only at doses above 2 Gy (Kook et al., 2015). This, however, is inconsistent with other studies performed at doses of 1-2 Gy, which indicate a significant effect of radiation on ROS production, TRAP expression, and ALP activity at lower doses (≤2 Gy) (Huang et al., 2018; Huang et al., 2019; Kondo et al., 2010; Zhang et al., 2020). Further research is needed to elucidate the effects of low doses, as well as the dose-dependent effect of increasing doses of ionizing radiation (IR).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating factor 

Details 

Effects on the KER 

References 

Drug 

α2M 

Treatment reversed the radiation-induced effects on ALP and SOD activity 

Liu et al., 2018 

Drug 

N-acetyl cysteine 

2.5 and 5 mM reversed the effects of 8 Gy radiation on ROS levels and ALP activity 

Kook et al., 2015 

Drug 

AMI 

Treatment with 30 mg/kg reversed the radiation-induced effects on ROS levels, ALP activity and TRAP-5b levels 

Huang et al., 2019; Zhang et al., 2020 

Drug 

CeO

Treatment with 100 nM lowered dihydroethidium (DHE) and H2O2 levels and partially restored Alizarin red optical density 

Wang et al., 2016 

Drug 

Sema3a 

Treatment with 50 ng/mL partially reduced ROS levels and reversed TRAP stain to below controls 

Huang et al., 2018 

Drug 

Curcumin (antioxidant) 

Fully reversed all oxidative stress and altered bone cell homeostasis 

Xin et al., 2015 

Drug 

Hydrogen water 

Reversed microgravity-induced effects on oxidative stress and altered bone cell homeostasis 

Sun et al., 2013 

Drug 

Polyphenol S3 

Fully reversed microgravity-induced oxidative stress, osteoblastogenesis and osteoclastogenesis 

Diao et al., 2018 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Dose/Incidence concordance 

Reference 

Experiment Description 

Result 

Huang et al., 2018 

In vitro. A single dose of 2 Gy 60Co gamma radiation by linear accelerator was administered to murine RAW264.7 osteoclast-like cells at a rate of 0.83 Gy/min. ROS production was measured to assess oxidative stress and TRAP staining was used to measure subsequent osteoclastogenic changes. 

2-fold increase in ROS production accompanied by a ~2-fold increase in the number of TRAP-positive cells in cells exposed to 2 Gy 60Co gamma radiation relative to controls. 

Huang et al., 2019 

Ex vivo. A single dose of 2 Gy 60Co gamma radiation was administered to bone marrow stromal stem cells of Sprague-Dawley rats at a rate of 0.83 Gy/min. ROS production was measured to assess oxidative stress and ALP activity was measured to determine subsequent imbalances in osteoblastogenesis. 

~2-fold increase in ROS production with a 0.33-fold decrease in ALP activity in cells exposed to 2 Gy 60Co gamma rays relative to unirradiated controls. 

  

Zhang et al., 2020 

In vitro. RAW264.7 cells were irradiated with 2 Gy of 60Co gamma radiation at a rate of 0.83 Gy/min was administered. ROS production was measured to assess oxidative stress and TRAP staining was used to measure subsequent changes to osteoclastogenesis. 

2-fold increase in ROS production in RAW264.7 cells and a 2-fold increase in the number of TRAP-positive osteoclasts when exposed to 2 Gy gamma radiation. 

  

Kondo et al., 2010 

In vivo. Male C57BL/6J mice at 17 weeks of age were hindlimb unloaded or normally loaded, 4 days later they were exposed to 1 or 2 Gy of 137Cs or sham irradiated. Oxidative stress markers including, ROS production, MDA, and 4-hydroxynonenal (4-HNE) were measured along with tibial osteoclast surface. 

In normally loaded mice, there was a ~1.3-fold increase in ROS at 1 Gy by day 3 and a ~1.2-fold increase in ROS at 2 Gy by day 10. There was a 2-fold increase in MDA and 4-HNE under exposure to either 1 or 2 Gy gamma radiation relative to control in normally loaded models by day 10. There was a 46%, 47% and 64% increase in tibiae osteoclast surface as a result of 2 Gy irradiation, hindlimb unloading and the combination of irradiation and hindlimb unloading, respectively. 

  

Kook et al., 2015 

In vitro. MC3T3-E1 cells were exposed to various doses of X-ray irradiation (0–8 Gy) at a rate of 1.5 Gy/min. Levels of ROS, superoxide dismutase (SOD), and glutathione (GSH) were measured to assess oxidative stress and ALP activity was measured to assess subsequent changes in osteoblastogenesis. 

Roughly linear dose-dependent increase from 0-8 Gy (significant increases at 4 and 8 Gy) in intracellular ROS accumulation up to 1.39-fold of the control at 8 Gy. Dose dependent decrease from 2-8 Gy (significant decreases at 4 Gy and 8 Gy) in SOD and GSH activity to half at 8 Gy.  

Following 8 Gy of IR, OCN mRNA expression decreased 48% compared to the non-irradiated control. Irradiation at 4 Gy showed similar decrease in OCN mRNA expression. Mouse bone marrow stromal cell ALP activity saw a significant, 0.62-fold decrease following 8 Gy irradiation. 

Liu et al., 2018 

In vitro. Human bone marrow-derived mesenchymal cells (hBMMSCs) were irradiated with X-rays at a dose of 2, 4, 8 and 12 Gy and a dose rate of 1.24 Gy/min. SOD levels were measured to assess oxidative stress. ALP activity, calcium deposition and hBMMSCs proliferation were determined. 

Following irradiation at 8 Gy, there was a ~0.5-fold decrease in osteoblast SOD activity. 

There was a dose-dependent decrease in hBMMSC proliferation following irradiation with 2, 4, 8, and 12 Gy, compared to the non-irradiated control. Changes in cell proliferation became significant at doses ≥8 Gy, with a maximum decrease of ~0.60-fold at 1 week-post irradiation with 12 Gy. 8 Gy of IR resulted in a 0.46 decrease in both ALP activity and calcium deposition compared to non-irradiated controls. 

Wang et al., 2016 

In vitro. MC3T3-E1 cells were exposed to X-ray irradiation at a dose of 6 Gy. Levels of ROS and H2O2 were measured along with ALP activity and calcium deposition. 

1.5-fold increase in H2O2 accumulation and 1.75-fold increase in ROS staining intensity under 6 Gy X-rays. Measured at 1-week post-irradiation, following 6 Gy of IR, there was a 0.54-fold decrease in ALP activity compared to the non-irradiated controls. Measured at 3 weeks post-irradiation, Alizarin Red staining revealed a ~0.1-fold decrease in calcium deposition following exposure to 6 Gy of IR. 

Xin et al., 2015 

In vivo and in vitro. Sprague-Dawley rats (8 weeks old) were hindlimb suspended and after six weeks, oxidative stress markers and altered bone cell homeostasis were measured. MC3T3-E1 cells and RAW264.7 cells were exposed to modeled microgravity in the NASA rotating wall vessel bioreactor (RWVB). Intracellular ROS and ALP and TRAP levels were measured. 

Rat femur MDA increased by ~1.4-fold. Rat femurs showed a ~2.5-fold increase in TRAP mRNA and a ~0.5-decrease in OCN mRNA.  

MC3T3-E1 cells found a ~1.3-fold increase in ROS formation and a ~0.75-fold decrease in ALP activity. RAW264.7 found a 2-fold increase in intracellular ROS and a 2-fold increase in TRAP positive osteoclasts. 

Sun et al., 2013 

In vivo and in vitro. Male Sprague–Dawley rats were subjected to hindlimb suspension for 6 weeks. RAW264.7 and MC3T3-E1 cells were exposed to modeled microgravity by RWVB (0.01xg). Femoral peroxynitrite (OONO-), MDA, and intracellular ROS were measured to assess oxidative stress and deoxypyridinoline (DPy), ALP levels, and TRAP-positive cells were subsequently measured to assess bone cell function. 

Rats exposed to microgravity via unloading of hindlimbs showed a 2.5-fold increase in femoral peroxynitrite (OONO-) and a 1.3-fold increase in femoral MDA. This was accompanied by a roughly 1.8-fold increase in DPy excretion (biomarker of bone resorption) and 0.4-fold decrease in femoral ALP expression. Exposure to modeled microgravity in MC3T3-E1 (osteoblast cell line) led to a ~1.4-fold increase in intracellular ROS and a 0.75-fold decrease in osteoblast ALP activity.  RAW264.7 (preosteoclast cell line) found a ~2-fold increase in ROS and a ~5-fold increase in TRAP mRNA expression. 

Diao et al., 2018 

In vivo. 50 Male Sprague-Dawley rats (6 weeks) were hindlimb suspended for 72 hours. SOD, catalase (CAT), and MDA were measured to assess oxidative stress and TRAP-5b, OCN and N-terminal type 1 collagen telopeptide (NTX) were measured to assess subsequent bone cell function. 

Rats under hindlimb suspension showed a ~0.4-fold decrease in SOD, ~0.3-fold decrease in CAT activity, and a ~1.5-fold increase in MDA relative to unloaded controls in rat femur. This was accompanied by ~1.14-fold increase in serum TRAP-5b and ~1.3-fold increase in NTX. 

Relative mRNA OCN levels and mRNA collagen I alpha 1 in rat femur decreased significantly. 

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Time concordance 

Reference 

Experiment Description 

Result 

Huang et al., 2018 

In vitro. A single dose of 2Gy 60Co gamma radiation was administered to murine RAW264.7 osteoclast-like cells at a rate of 0.83 Gy/min. ROS production was measured to assess oxidative stress and TRAP staining was used to measure subsequent changes in osteoclastogenesis. 

2-fold increase in ROS production after 2h accompanied by a ~2-fold increase in the number of TRAP-positive cells after 7 days in cells exposed to 2 Gy gamma radiation relative to controls. 

Kondo et al., 2010 

In vivo. Male C57BL/6J at 17 weeks of age were hindlimb unloaded or normally loaded, 4 days later they were exposed to 1 or 2 Gy of 137Cs or sham irradiated. Oxidative stress markers including, ROS production, MDA, and 4-HNE were measured along with tibial osteoclast surface. 

In normally loaded mice, at day 3, ROS in the 1 Gy group increased significantly. By day 10, however, ROS in the 1 Gy group had dropped relative to day 3, while ROS in the 2 Gy group reached significant levels compared to the control. Also, by day 10, MDA and 4-HNE increased ~2-fold in normally loaded mice. This was accompanied by a 46% increase in tibiae osteoclast surface due to irradiation at day 3. 

Kook et al., 2015 

In vitro. MC3T3-E1 cells were exposed to various doses of X-ray radiation (0–8 Gy) at a rate of 1.5 Gy/min. Levels of ROS, SOD, and GSH were measured to assess oxidative stress and ALP activity was measured to assess subsequent changes in osteoblastogenesis. 

Roughly linear dose-dependent increase (after 2 Gy X-ray radiation) in intracellular ROS accumulation up to 1.39-fold of the control at 8 Gy after 1 day. Dose dependent decrease (after 2 Gy) in SOD and GSH activity to half at 8 Gy after 1 day.  

Markers for altered bone cell homeostasis were measured at 7 days post-irradiation. Following 8 Gy of IR, OCN mRNA expression decreased 48% compared to the non-irradiated control. Irradiation at 4 Gy showed similar decrease in OCN mRNA expression. Mouse bone marrow stromal cell ALP activity saw a significant, 0.62-fold decrease following 8 Gy irradiation. 

Liu et al., 2018 

In vitro. hBMMSCs were irradiated with X-rays at dose of 2, 4, 8 and 12 Gy, and a dose rate of 1.24 Gy/min. SOD levels were measured to assess oxidative stress. ALP activity, calcium deposition and hBMMSCs proliferation were determined. 

0.5-fold decrease in osteoblast SOD activity after 1 day with 0.46-fold decrease in ALP activity after 1 week.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not Identified

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The evidence for the taxonomic applicability to humans is low as majority of the evidence is from in vitro human-derived cells. The relationship is supported by mice and rat models using male and female animals. The relationship is plausible at any life stage. However, most studies have used adolescent and adult animal models

References

List of the literature that was cited for this KER description. More help

Almeida, M. (2011), “Unraveling the role of FoxOs in bone--insights from mouse models.” Bone vol. 49,3: 319-27. https://doi.org/10.1016/j.bone.2011.05.023 

Bartell, S. M. et al. (2014), "FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation", Nature Communications, Vol. 5/1, Nature, https://doi.org/10.1038/ncomms4773

Diao, Y. et al. (2018), "Polyphenols (S3) Isolated from Cone Scales of Pinus koraiensis Alleviate Decreased Bone Formation in Rat under Simulated Microgravity", Scientific Reports, Vol. 8/1, Nature https://doi.org/10.1038/s41598-018-30992-8

Donaubauer, A.-J. et al. (2020), "The Influence of Radiation on Bone and Bone Cells—Differential Effects on Osteoclasts and Osteoblasts", International Journal of Molecular Sciences, Vol. 21/17, MDPI, Basel, https://doi.org/10.3390/ijms21176377

Huang, B. et al. (2019), "Amifostine suppresses the side effects of radiation on BMSCs by promoting cell proliferation and reducing ROS production", Stem Cells International, Vol. 2019, Hindawi, https://doi.org/10.1155/2019/8749090

Huang, B. et al. (2018), "Sema3a inhibits the differentiation of raw264.7 cells to osteoclasts under 2gy radiation by reducing inflammation", PLoS ONE, Vol. 13/7, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0200000

Kondo, H. et al. (2010), "Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse", Journal of Applied Physiology, Vol. 108/1, American Physiological Society, https://doi.org/10.1152/japplphysiol.00294.2009

Kook, S. H. et al. (2015), "Irradiation inhibits the maturation and mineralization of osteoblasts via the activation of Nrf2/HO-1 pathway", Molecular and Cellular Biochemistry, Vol. 410/1–2, Nature, https://doi.org/10.1007/s11010-015-2559-z

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306

Liu, Y. et al. (2018), "Protective Effects of α‑2‑Macroglobulin on Human Bone Marrow Mesenchymal Stem Cells in Radiation Injury", Molecular Medicine Reports, Vol. 18/5, Spanditos Publications, https://doi.org/10.3892/mmr.2018.9449

Maeda, K. et al. (2019), "The Regulation of Bone Metabolism and Disorders by Wnt Signaling", International Journal of Molecular Sciences, Vol. 20/22, MDPI, Basel, https://doi.org/10.3390/ijms20225525

Manolagas, S. C. and M. Almeida. (2007), "Gone with the Wnts: β-Catenin, T-Cell Factor, Forkhead Box O, and Oxidative Stress in Age-Dependent Diseases of Bone, Lipid, and Glucose Metabolism”, Molecular Endocrinology, Vol. 21/11, Oxford University Press, Oxford, https://doi.org/10.1210/me.2007-0259

Sun, Y. et al. (2013), "Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats", Osteoporosis International, Vol. 24/3, Nature, https://doi.org/10.1007/s00198-012-2028-4

Tahimic, C. G. T. and R. K. Globus. (2017), "Redox signaling and its impact on skeletal and vascular responses to spaceflight", International Journal of Molecular Sciences, Vol. 18/10, MDPI, Basel, https://doi.org/10.3390/ijms18102153

Tian, Y. et al. (2017), "The impact of oxidative stress on the bone system in response to the space special environment", International Journal of Molecular Sciences, Vol. 18/10, MDPI, Basel, https://doi.org/10.3390/ijms18102132

Wang, C. et al. (2016), "Protective effects of cerium oxide nanoparticles on MC3T3-E1 osteoblastic cells exposed to X-ray irradiation", Cellular Physiology and Biochemistry, Vol. 38/4, Karger, Basel, https://doi.org/10.1159/000443092

Xin, M. et al. (2015), "Attenuation of hind-limb suspension-induced bone loss by curcumin is associated with reduced oxidative stress and increased vitamin D receptor expression", Osteoporosis International, Vol. 26/11, Nature, https://doi.org/10.1007/s00198-015-3153-7

Zhang, L. et al. (2020), "Amifostine inhibited the differentiation of RAW264.7 cells into osteoclasts by reducing the production of ROS under 2 Gy radiation", Journal of Cellular Biochemistry, Vol. 121/1, Wiley, https://doi.org/10.1002/jcb.29247