Deferoxamine alleviates chondrocyte senescence and osteoarthritis progression by maintaining iron homeostasis.

BACKGROUND: Osteoarthritis (OA) is a prevalent age-related disease characterized by the gradual deterioration of cartilage. The involvement of chondrocyte senescence is crucial in the pathogenesis of OA. Desferoxamine (DFO) is an iron chelator with therapeutic potential in various diseases. However, the relationship of chondrocyte senescence and iron homeostasis is largely unknown. METHODS: Chondrocyte senescence was induced using tert-butyl hydroperoxide (TBHP), and the impact of DFO on chondrocyte senescence and iron metabolism was assessed through techniques such as western blotting, qRT-PCR, and ß-Galactosidase staining. To assess the impact of DFO on chondrocyte senescence and the progression of osteoarthritis (OA), the surgical destabilization of the medial meniscus model was established. RESULTS: In chondrocytes, TBHP administration resulted in elevated expression of P16, P21, and P53, as well as alterations in SA-ß-gal staining. Nevertheless, DFO effectively mitigated chondrocyte senescence induced by TBHP, and reversed the decrease in collagen II expression and increase in MMP13 expression caused by TBHP. Mechanismly, TBHP induced NCOA4 expression and iron release in chondrocytes. Excessive iron could induce chondrocyte senescence, whereas, DFO could inhibit NCOA4 expression and restore ferritin level, and chelate excessive iron. Importantly, intra-articular injection of DFO enhanced collagen II expression and reduced expression of P16, P21, and MMP13 of cartilage in OA mice, and delayed cartilage degeneration. CONCLUSIONS: Overall, this study provides evidence that DFO has the potential to alleviate chondrocyte senescence induced by TBHP and slow down the progression of osteoarthritis (OA) by effectively chelating excessive iron. These findings suggest that iron chelation could be a promising therapeutic strategy for treating OA.

IRF1 regulation of ZBP1 links mitochondrial DNA and chondrocyte damage in osteoarthritis.

BACKGROUND: Z-DNA binding protein 1 (ZBP1) is a nucleic acid sensor that is involved in multiple inflammatory diseases, but whether and how it contributes to osteoarthritis (OA) are unclear. METHODS: Cartilage tissues were harvested from patients with OA and a murine model of OA to evaluate ZBP1 expression. Subsequently, the functional role and mechanism of ZBP1 were examined in primary chondrocytes, and the role of ZBP1 in OA was explored in mouse models. RESULTS: We showed the upregulation of ZBP1 in articular cartilage originating from OA patients and mice with OA after destabilization of the medial meniscus (DMM) surgery. Specifically, knockdown of ZBP1 alleviated chondrocyte damage and protected mice from DMM-induced OA. Mechanistically, tumor necrosis factor alpha induced ZBP1 overexpression in an interferon regulatory factor 1 (IRF1)-dependent manner and elicited the activation of ZBP1 via mitochondrial DNA (mtDNA) release and ZBP1 binding. The upregulated and activated ZBP1 could interact with receptor-interacting protein kinase 1 and activate the transforming growth factor-beta-activated kinase 1-NF-κB signaling pathway, which led to chondrocyte inflammation and extracellular matrix degradation. Moreover, inhibition of the mtDNA-IRF1-ZBP1 axis with Cyclosporine A, a blocker of mtDNA release, could delay the progression of DMM-induced OA. CONCLUSIONS: Our data revealed the pathological role of the mtDNA-IRF1-ZBP1 axis in OA chondrocytes, suggesting that inhibition of this axis could be a viable therapeutic approach for OA.

Genomic Insights into the Role of TOP Gene Family in Soft-Tissue Sarcomas: Implications for Prognosis and Therapy.

This study focuses on the role of topoisomerases (TOPs) in sarcomas (SARCs), highlighting TOPs' influence on sarcoma prognosis through mRNA expression, genetic mutations, immune infiltration, and DNA methylation analysis using transcriptase sequencing and other techniques. The findings indicate that TOP gene mutations correlate with increased inflammation, immune cell infiltration, DNA repair abnormalities, and mitochondrial fusion genes alterations, all of which negatively affect sarcoma prognosis. Abnormal TOP expression may independently affect sarcoma patients' survival. Cutting-edge genomic tools such as Oncomine, gene expression profiling interactive analysis (GEPIA), and cBio Cancer Genomics Portal (cBioPortal) are utilized to explore the TOP gene family (TOP1/1MT/2A/2B/3A/3B) in soft-tissue sarcomas (STSs). This in-depth analysis reveals a notable upregulation of TOP mRNA in STS patients arcoss various SARC subtypes, French Federation Nationale des Centres de Lutte Contre le Cancer classification (FNCLCC) grades, and specific molecular profiles correlating with poorer clinical outcomes. Furthermore, this investigation identifies distinct patterns of immune cell infiltration, genetic mutations, and somatic copy number variations linked to TOP genes that inversely affect patient survival rates. These findings underscore the diagnostic and therapeutic relevance of the TOP gene suite in STSs.

SEPT3 as a Potential Molecular Target of Triple-Negative Breast Cancer.

Background: The survival rate for triple-negative breast cancer (TNBC) is very low due to its advanced metastatic and aggressive nature, and there is no specific target to improve the survival rate. The expression and clinical signature of neuronal-specific septin-3 (Septin3, SEPT3) in TNBC remain undetermined. Methods: SEPT3 differential expression in TNBC was detected with the use of bioinformatic approaches based on TCGA and GEO database, which was verified with immunohistochemistry in TNBC tissues. Next, the effect of SEPT3 on survival and the association between SEPT3 expression and clinical characteristics were assessed for TNBC patients. We performed Cox analysis to evaluate whether SEPT3 is an independent predictor for TNBC patients. Results: SEPT3 was identified as a key differentially expressed gene. SEPT3 was observed to be elevated in 112 TNBC significantly. Increased expression of SEPT3 contributed to an unfavorable prognosis in patients with TNBC. Additionally, SEPT3 was associated with several factors including TNM stage, lymph node metastasis, Ki67 level and histological grade. SEPT3 was determined to be an independent risk factor for TNBC patients through Cox regression analysis. Conclusion: This study demonstrated that SEPT3 could be a potential disease marker for TNBC patients by bioinformatics analysis and validation in clinical samples.

Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway.

Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1ß (IL-1ß) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1ß and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1ß and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA.

Erratum: Mitoquinone alleviates osteoarthritis progress by activating the NRF2-Parkin axis.

[This corrects the article DOI: 10.1016/j.isci.2023.107647.].

DMT1-mediated iron overload accelerates cartilage degeneration in Hemophilic Arthropathy through the mtDNA-cGAS-STING axis.

INTRODUCTION: Excess iron contributes to Hemophilic Arthropathy (HA) development. Divalent metal transporter 1 (DMT1) delivers iron into the cytoplasm, thus regulating iron homeostasis. OBJECTIVES: We aimed to investigate whether DMT1-mediated iron homeostasis is involved in bleeding-induced cartilage degeneration and the molecular mechanisms underlying iron overload-induced chondrocyte damage. METHODS: This study established an in vivo HA model by puncturing knee joints of coagulation factor VIII gene knockout mice with a needle, and mimicked iron overload conditions in vitro by treatment of Ferric ammonium citrate (FAC). RESULTS: We demonstrated that blood exposure caused iron overload and cartilage degeneration, as well as elevated expression of DMT1. Furthermore, DMT1 silencing alleviated blood-induced iron overload and cartilage degeneration. In hemophilic mice, articular cartilage degeneration was also suppressed by intro-articularly injection of DMT1 adeno-associated virus 9 (AAV9). Mechanistically, RNA-sequencing analysis indicated the association between iron overload and cGAS-STING pathway. Further, iron overload triggered mtDNA-cGAS-STING pathway activation, which could be effectively mitigated by DMT1 silencing. Additionally, we discovered that RU.521, a potent Cyclic GMP-AMP Synthase (cGAS) inhibitor, successfully suppressed the downward cascades of cGAS-STING, thereby protecting against chondrocyte damage. CONCLUSION: Taken together, DMT1-mediated iron overload promotes chondrocyte damage and murine HA development, and targeted DMT1 may provide therapeutic and preventive approaches in HA.

P21 resists ferroptosis in osteoarthritic chondrocytes by regulating GPX4 protein stability.

Ferroptosis is involved in the pathogenesis of osteoarthritis (OA) while suppression of chondrocyte ferroptosis has a beneficial effect on OA. However, the molecular mechanism of ferroptosis in OA remains to be elucidated. P21, an indicator of aging, has been reported to inhibit ferroptosis, but the relationship between P21 and ferroptosis in OA remains unclear. Here, we aimed to investigate the expression and function of P21 in OA chondrocytes, and the involvement of P21 in the regulation of ferroptosis in chondrocytes. First, we demonstrated that high P21 expression was observed in the cartilage from OA patients and destabilized medial meniscus (DMM) mice, and in osteoarthritic chondrocytes induced by IL-1ß, FAC and erastin. P21 knockdown exacerbated the reduction of Col2a1 and promoted the upregulation of MMP13 in osteoarthritic chondrocytes. Meanwhile, P21 knockdown exacerbated cartilage degradation in DMM-induced OA mouse models and decreased GPX4 expression in vivo. Furthermore, P21 knockdown sensitized chondrocytes to ferroptosis induced by erastin, which was closely associated with the accumulation of lipid peroxides. In mechanism, we demonstrated that P21 regulated the stability of GPX4 protein, and the regulation was independent of NRF2. Meanwhile, we found that P21 significantly affected the recruitment of GPX4 to linear ubiquitin chain assembly complex (LUBAC) and regulated the level of M1-linked ubiquitination of GPX4. Overall, our results suggest that P21 plays an essential anti-ferroptosis role in OA by regulating the stability of GPX4.

Stimuli-responsive grating with a tunable period and a diffraction order.

The next-generation diffraction grating not only requires a nonmechanical control and a remote control to generate a diffraction pattern but also requires a tunable period. Here, we propose a stimuli-responsive liquid crystal (LC) phase grating with a tunable period and a diffraction order. The stimuli-responsive LC diffraction grating is composed of periodically arranged electrodes on a double-sided glass substrate. By adjusting the driving scheme, the pitch and diffraction order of the LC grating can be switched between three different modes. The experimental results show that the LC grating has a lower driving voltage (∼5 V). In addition, the tunable LC grating can achieve more diffraction orders, which can be applied to a holographic display to achieve a wide-viewing angle and an enlarged size.

A novel sample preparation method based on polarity grouping for comprehensive determination of 315 pesticides and other contaminants in wolfberry by liquid chromatography-tandem mass spectrometry.

A novel sample preparation method based on polarity grouping was developed for the comprehensive determination of 315 undesirable low-weight organic pollutants ranging from polar to weakly polar in wolfberry. The method involves the swelling of the sample in ammonium acetate buffer, two-phase extraction, three-phase extraction, and dispersive solid phase extraction (D-SPE) with the assistance of low-temperature centrifugation and analysis by ultrahigh performance liquid chromatography coupled with electrospray ionization tandem mass (UHPLC-ESI-MS-MS) by using the multiple reaction monitoring mode. The recoveries of the analytes with wide range of polarity were satisfactory. The matrix-fortified standard calibration curves were compared for quantification. The results of linearity were satisfactory with linear regression coefficients (R) ranging from 0.9901 to 1.000. The limits of quantification ranged from 1 µg/kg to 10.0 µg/kg, indicating the compliance of products with legal tolerances. The average recoveries for spiked wolfberry were in the range of 69.3 %-145.2 % with RSD values of 0.2 %-28.6 %. The inter-day precision was in the range of 0.2 %-27.0 %. For over 90 % of the analytes, the recoveries were 70 %-120 % with RSD values below 20 %. The application of this method in routine monitoring programs would imply a drastic reduction of both effort and time.

Risk factors for post-traumatic stress disorder among young and middle-aged cancer patients in the intensive care unit: A case-control study.

BACKGROUND: Young and middle-aged cancer patients in intensive care unit (ICU) often suffer from stress and pressure, causing huge physical and mental damage. Currently, there is few research on post-traumatic stress disorder (PTSD) among young and middle-aged cancer patients in ICU in China, and the psychological status of patients who have experienced both cancer development and ICU stay is still unclear. AIM: To explore the risk factors for PTSD in young and middle-aged patients with cancer in ICU. METHODS: Using convenient sampling method, we enrolled 150 young and middle-aged patients with cancer who were admitted to the ICU of our center during the period from July to December 2020. The general data of the patients and PTSD-related indicators were collected. The Impact of Event Scale-Revised (IES-R) was used for assessing PTSD one month after the discharge from the ICU. Binary Logistic regression analysis was performed to assess the independent risk factors for PTSD in these patients. RESULTS: Among these 150 patients, 32 (21.33%) were found to be with PTSD. Binary Logistic regression analysis revealed that factors significantly associated with PTSD among young and middle-aged patients with cancer in ICU included monthly income (OR = 0.24, P = 0.02), planned transfers (OR = 0.208, P = 0.019), and Acute Physiology and Chronic Health Evaluation (APACHE II) score (OR = 1.171, P = 0.003). CONCLUSION: The low monthly income, unplanned transfers, and increased APACHE II score are the risk factors for PTSD in young and middle-aged patients with cancer in ICU.

Mitoquinone alleviates osteoarthritis progress by activating the NRF2-Parkin axis.

Osteoarthritis (OA) is a prevalent degenerative disease of the elderly. The NRF2 antioxidant system plays a critical role in maintaining redox balance. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant. This research aimed to determine whether MitoQ alleviated OA and the role of the NRF2/Parkin axis in MitoQ-mediated protective effects. In interleukin (IL)-1ß-induced OA chondrocytes, MitoQ activated the NRF2 pathway, reducing extracellular matrix (ECM) degradation and inflammation. MitoQ also increased glutathione peroxidase 4 (GPX4) expression, leading to decreased levels of reactive oxygen species (ROS) and lipid ROS. Silencing NRF2 weakened MitoQ's protective effects, while knockdown of Parkin upregulated the NRF2 pathway, inhibiting OA progression. Intra-articular injection of MitoQ mitigated cartilage destruction in destabilized medial meniscus (DMM)-induced OA mice. Our study demonstrates that MitoQ maintains cartilage homeostasis in vivo and in vitro through the NRF2/Parkin axis. We supplemented the negative feedback regulation mechanism between NRF2 and Parkin. These findings highlight the therapeutic potential of MitoQ for OA treatment.

SEPTIN3 Promotes Progression of Triple-Negative Breast Cancer via Activating Wnt Pathway.

Background: There is a lack of targeted therapies for triple-negative breast cancer (TNBC), necessitating the search for novel targets. Patients with TNBC exhibit elevated expression of neuron-specific septin-3 (SEPTIN3), leading to poor prognosis. This study aimed to investigate the modulation of SEPTIN3 expression in TNBC cells. Methods: The relative expression levels of SEPTIN3 in TNBC tissues and cell lines were determined using Western blotting and qRT-PCR. We generated lentivirally transduced TNBC cell lines so such that SEPTIN3 was overexpressed or knocked down. Next, the effect of SEPTIN3 on the biological behavior of TNBC cells was detected using a series of functional assays, including CCK8, colony formation, scratch, and transwell assays. We monitored the tumorigenicity of SEPTIN3 overexpressed cells and performed Ki-67 immunostaining in mice. The mechanism mediated by SEPTIN3 was studied using functional enrichment analysis and Western blotting. Results: Protein and mRNA expression levels of SEPTIN3 were observed to be increased in TNBC tissues and cell lines. SEPTIN3 knockdown reduced cell growth, invasion, and migration, whereas SEPTIN3 overexpression exerted the opposite effects. SEPTIN3 was observed to favor cell growth and tumorigenicity in vivo. In addition, SEPTIN3 promoted TNBC cell aggressiveness and proliferation via activation of the Wnt signaling pathway. Conclusion: SEPTIN3 emerged as an oncogene that accelerates tumor progression by regulating the Wnt signaling pathway.

Lipid peroxidation in osteoarthritis: focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis.

Osteoarthritis (OA) is a multifactorial and increasingly prevalent degenerative disease that affects the whole joint. The pathogenesis of OA is poorly understood and there is a lack of therapeutic interventions to reverse the pathological process of this disease. Accumulating studies have shown that the overproduction of reactive oxygen species (ROS) and ROS-induced lipid peroxidation are involved in the pathogenesis of OA. 4-Hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) have received considerable attention for their role in cartilage degeneration and subchondral bone remodeling during OA development. Ferroptosis is a form of cell death characterized by a lack of control of membrane lipid peroxidation and recent studies have suggested that chondrocyte ferroptosis contributes to OA progression. In this review, we aim to discuss lipid peroxidation-derived 4-HNE and MDA in the progression of OA. In addition, the therapeutic potential for OA by controlling the accumulation of lipid peroxidation and inhibiting chondrocyte ferroptosis are discussed.

The roles of the Hippo-YAP signalling pathway in Cartilage and Osteoarthritis.

Osteoarthritis (OA) is an age-related disease, characterized by cartilage degeneration. The pathogenesis of OA is complicated and the current therapeutic approaches for OA are limited. Cartilage, an integral part of the skeletal system composed of chondrocytes, is essential for skeletal development, tissue patterning, and maintaining the normal activity of joints. The development, homeostasis and degeneration of cartilage are tightly associated with OA. Over the past decade, accumulating evidence indicates that Hippo/YAP is a vital biochemical signalling pathway that strictly governs tissue development and homeostasis. The joint tissues, especially for cartilage, are sensitive to changes of Hippo/YAP signalling. In this review, we summarize the role of Hippo/YAP signalling in cartilage and discuss its involvement in OA progression from points of cartilage degradation, subchondral bone remodeling, and synovial alteration. We also highlight the potential therapeutic implications of Hippo/YAP signalling and further discuss current limitations and controversy on Hippo/YAP-based application for OA treatment.

Corrigendum: Deferoxamine alleviates osteoarthritis by inhibiting chondrocyte ferroptosis and activating the Nrf2 pathway.

[This corrects the article DOI: 10.3389/fphar.2022.791376.].

JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy.

Interruption of iron homeostasis is correlated with cell ferroptosis and degenerative diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been reported as a vital mechanism to control cellular iron levels, but its impact on osteoarthritis (OA) pathology and the underline mechanism are unknown. Herein we aimed to investigate the role and regulatory mechanism of NCOA4 in chondrocyte ferroptosis and OA pathogenesis. We demonstrated that NCOA4 was highly expressed in cartilage of patients with OA, aged mice, post-traumatic OA mice, and inflammatory chondrocytes. Importantly, Ncoa4 knockdown inhibited IL-1ß-induced chondrocyte ferroptosis and extracellular matrix degradation. Contrarily, overexpression of NCOA4 promoted chondrocyte ferroptosis and the delivery of Ncoa4 adeno-associated virus 9 into knee joint of mice aggravated post-traumatic OA. Mechanistic study revealed that NCOA4 was upregulated in a JNK-JUN signaling-dependent manner in which JUN could directly bind to the promoter of Ncoa4 and initial the transcription of Ncoa4. NCOA4 could interact with ferritin and increase autophagic degradation of ferritin and iron levels, which caused chondrocyte ferroptosis and extracellular matrix degradation. In addition, inhibition of JNK-JUN-NCOA4 axis by SP600125, a specific inhibitor of JNK, attenuated development of post-traumatic OA. This work highlights the role of JNK-JUN-NCOA4 axis and ferritinophagy in chondrocyte ferroptosis and OA pathogenesis, suggesting this axis as a potential target for OA treatment.

Inhibition of TRADD ameliorates chondrocyte necroptosis and osteoarthritis by blocking RIPK1-TAK1 pathway and restoring autophagy.

Osteoarthritis (OA) is an age-related disease characterized by cartilage degeneration. TNFR1-associated death domain protein (TRADD) is a key upstream molecule of TNF-α signals but its role in OA pathogenesis is unknown. This study aimed to verify that whether inhibition of TRADD could protect against chondrocyte necroptosis and OA, and further elucidate the underlying mechanism. We demonstrated that TNF-α-related OA-like phenotypes including inflammation response, extracellular matrix degradation, apoptosis, and necroptosis in chondrocytes were inhibited by TRADD deficiency. Furthermore, TRADD interacted with TRAF2 and knockdown of TRADD suppressed the activation of RIPK1-TAK1-NF-κB signals and restored impaired autophagy. ICCB-19, the selective inhibitor of TRADD, also attenuated necroptosis in chondrocytes. Mechanismly, ICCB-19 blocked the phosphorylation of TAK1-NF-κB signals and restored impaired autophagy, whereas inhibiting autophagic process with 3-Methyladenine compromised these effects of ICCB-19. The in vivo study showed that the intra-articular injection of ICCB-19 rescued the expression of collagen alpha-1(II) chain and LC3, and mitigated the cartilage degeneration of OA mice. This study demonstrates that TRADD mediates TNF-α-induced necroptosis and OA-like phenotypes of chondrocytes and suggests that ICCB-19 suppresses chondrocyte damage and cartilage degeneration by inhibiting TNF-α-TRADD-mediated signals and dysregulation of autophagy in chondrocytes. ICCB-19 may serve as an important option for OA therapy.

Design and experiment of a combined peeling machine for water chestnut.

Water chestnut is a characteristic aquatic vegetable in China, and its demand for peeling fresh fruit is increasing rapidly. Aiming at the existing problems of high labor intensity and low efficiency of manual peeling, a combined water chestnut peeling machine was designed, which used a rotary knife to remove bud and root, and a differential friction belts to remove side peel. The performance of the peeling machine was tested with water chestnut from Xiaogan, Hubei Provence. Under the conditions of 200 g feeding mass and 10 r/min rotation speed, the single factor test was carried out with cutting speed as the influencing factor and the cutting rate of bud and root as the evaluation index. The results showed that the cutting rate of fresh fruit of water chestnut bud and root were 79.04% and 83.77% respectively when the cutting speed of rotary knife was 1.2 m/s. In the differential friction belts, high and low linear velocities were taken as the influencing factors, and the side peel removal rate was used as the evaluation index. The side peel removal rate was 84.93% at the high-speed linear velocity of 2.1 m/s and the low-speed linear velocity of 1.58 m/s. The performance of the whole machine was evaluated, and the results showed that the working loss of the combined water chestnut peeling machine was 43.03% and the comprehensive peeling rate was 77.43%, which reached the design requirements. This study can provide a reference for the research and development of water chestnut peeling device.

Probucol suppresses osteoclastogenesis via activating Nrf2 signaling and ameliorates ovariectomy-induced bone loss.

Osteoporosis is a systemic and endocrine bone disorder distinguished by declined bone mineral density, compromised bone strength, and destruction of trabecular structure. The abnormally excessive osteoclastogenesis and bone erosion play imperative roles in the progression of osteoporosis. However, treatment of osteoporosis is far from satisfactory due to poor adherence to existing medications and adverse reactions, there is an urgent to develop novel therapies for osteoporosis. Probucol, a synthetic compound with two characteristic phenolic rings, owns anti-inflammatory and antioxidant properties. Accumulating evidence have indicated that intracellular reactive oxygen species (ROS) is closely related to osteoclastogenesis. Hence, we investigated the potential effects of probucol on osteoclastogenesis in vivo and in vitro. In this study, TRAP staining and bone slice resorption assay showed that probucol suppressed RANKL-induced osteoclast formation and function. The mRNA and protein levels of osteoclastogenesis marker genes were reduced by probucol in a concentration-dependent manner. Besides, probucol suppressed osteoclast differentiation by inhibiting ROS production, MAPKs and NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of probucol on osteoclast formation and function. Consistent with the above findings, in vivo experiments demonstrated that probucol visibly alleviated bone loss caused by estrogen deficiency. In brief, these results showed the potential of anti-oxidant compound probucol in the treatment of osteoporosis, highlighting Nrf2 as a promising target in osteoclast-related disease.