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1.
Cell Commun Signal ; 22(1): 366, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39026271

RESUMO

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.


Assuntos
Condrócitos , DNA Mitocondrial , Fator Regulador 1 de Interferon , Osteoartrite , Proteínas de Ligação a RNA , Condrócitos/metabolismo , Condrócitos/patologia , Animais , Osteoartrite/patologia , Osteoartrite/metabolismo , Osteoartrite/genética , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Humanos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Transdução de Sinais , Modelos Animais de Doenças
2.
Bone Joint Res ; 13(3): 110-123, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38447596

RESUMO

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.

3.
iScience ; 27(2): 108888, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38303700

RESUMO

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

4.
Biochim Biophys Acta Mol Basis Dis ; 1870(4): 167058, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38331112

RESUMO

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.


Assuntos
Sobrecarga de Ferro , Artropatias , Animais , Camundongos , Cartilagem , DNA Mitocondrial/genética , Ferro/metabolismo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Camundongos Knockout , Nucleotidiltransferases/metabolismo
5.
Free Radic Biol Med ; 212: 336-348, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38176476

RESUMO

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.


Assuntos
Ferroptose , Osteoartrite , Humanos , Camundongos , Animais , Condrócitos/metabolismo , Ferroptose/genética , Cartilagem/metabolismo , Modelos Animais de Doenças , Regulação para Cima , Osteoartrite/genética , Osteoartrite/metabolismo
6.
iScience ; 26(9): 107647, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37694150

RESUMO

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.

7.
Cell Death Discov ; 9(1): 320, 2023 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-37644030

RESUMO

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.

8.
J Vis Exp ; (191)2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36688553

RESUMO

Transiliac-transsacral screw fixation is challenging in clinical practice as the screws need to break through six layers of cortical bone. Transiliac-transsacral screws provide a longer lever arm to withstand the perpendicular vertical shear forces. However, the screw channel is so long that a minor discrepancy can lead to iatrogenic neurovascular injuries. The development of medical robots has improved the precision of surgery. The present protocol describes how to use a new teleoperated robotic system to execute transiliac-transacral screw fixation. The Robot was operated remotely to position the entry point and adjust the orientation of the sleeve. The screw positions were evaluated using postoperative computed tomography (CT). All the screws were safely implanted, as confirmed using intraoperative fluoroscopy. Postoperative CT confirmed that all the screws were in the cancellous bone. This system combines the doctor's initiative with the Robot's stability. The remote control of this procedure is possible. Robot-assisted surgery has a higher position-retention capacity compared with conventional methods. In contrast to active robotic systems, surgeons have full control over the operation. The robot system is fully compatible with operating room systems and does not require additional equipment.


Assuntos
Fixação Interna de Fraturas , Procedimentos Cirúrgicos Robóticos , Fixação Interna de Fraturas/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Parafusos Ósseos , Fluoroscopia/métodos , Tomografia Computadorizada por Raios X , Estudos Retrospectivos
9.
Life Sci ; 312: 121172, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36410411

RESUMO

AIMS: Hemophilic arthropathy (HA) is a typically iron overload induced joint disease secondary to continuous joint bleeding, however, the exact role of iron chelators in HA has not been fully elucidated. In the present study, we investigated whether desferoxamine (DFO), an iron chelator, could limit the development of HA and the underlying mechanisms. MATERIALS AND METHODS: A HA mice model was established by needle puncture in the left knees of FVIII-deficient hemophilic mice. HA progression was evaluated at 8 weeks after DFO administration. Moreover, chondrocytes were treated with ferric ammonium citrate (FAC) to mimic iron overload in vitro. Modulating effect of DFO on iron overload induced oxidative stress, chondrocytes apoptosis and extracellular matrix (ECM) degradation and the role of HIF-1α-BNIP3 mediated mitophagy were examined. KEY FINDINGS: We found that DFO limited the development of HA and protected iron overload induced ECM degradation, chondrocytes apoptosis and oxidative stress. Besides chelating Fe2+, we found that HIF-1α-BNIP3 mediated mitophagy played important roles in the protective effect of DFO. HIF-1α inhibition suppressed chondrocytes mitophagy process and partly diminished the protective effect of DFO on chondrocytes iron overload. SIGNIFICANCE: In conclusion, DFO could protect against HA development via HIF-1α-BNIP3 mediated mitophagy, suggesting DFO might be a potential therapeutic supplement for HA treatment.


Assuntos
Sobrecarga de Ferro , Artropatias , Camundongos , Animais , Regulação para Cima , Mitofagia , Quelantes de Ferro/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sobrecarga de Ferro/tratamento farmacológico , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo
10.
J Orthop Surg Res ; 16(1): 89, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509244

RESUMO

BACKGROUND: The transiliac-transsacral screw placement is a clinical challenge for surgeons. This study explored a point-to-point coaxial guide apparatus assisting the transiliac-transsacral screw insertion and aimed to investigate the feasibility and accuracy of the guide apparatus in the treatment of posterior ring unstable pelvic fracture compared with a free-hand technique. METHODS: A retrospective study was performed to evaluate patients treated with transiliac-transsacral screws assisted by the point-to-point coaxial guide apparatus or free-hand technique. The intraoperative data of operative time and radiation exposure times were recorded. Postoperative radiographs and CT scans were performed to scrutinize the accuracy of screws position. The quality of the postoperative fracture reduction was assessed according to Matta radiology criteria. The pelvic function was assessed according to the Majeed scoring criteria at 6 months postoperatively. RESULTS: From July 2017 to December 2019, a total of 38 patients were included in this study, 20 from the point-to-point guide apparatus group and 18 from the free-hand group. There were no significant differences between the two groups in gender, age, injury causes, pelvic fracture type, screws level, and follow-up time (P > 0.05). The average operative time of the guide apparatus group for each screw was significantly less than that in the free-hand group (25.8 ± 4.7 min vs 40.5 ± 5.1, P < 0.001). The radiation exposure times were significantly lower in the guide apparatus group than that in the free-hand group (24.4 ± 6.0 vs 51.6 ± 8.4, P < 0.001). The intraosseous and juxtacortical rate of screw placement (100%) higher than in the free-hand group (94.4%). CONCLUSION: The point-to-point coaxial guide apparatus is feasible for assisting the transiliac-transsacral screw in the treatment of posterior unstable pelvic fractures. It has the advantages of simple operation, reasonable design and no need for expensive equipment, and provides an additional surgical strategy for the insertion of the transiliac-transsacral screw.


Assuntos
Parafusos Ósseos , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/cirurgia , Fraturas não Consolidadas/cirurgia , Ossos Pélvicos/lesões , Ossos Pélvicos/cirurgia , Adulto , Feminino , Seguimentos , Fixação Interna de Fraturas/instrumentação , Fraturas Ósseas/diagnóstico por imagem , Fraturas não Consolidadas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Ossos Pélvicos/diagnóstico por imagem , Qualidade da Assistência à Saúde , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
11.
J Cell Mol Med ; 21(10): 2441-2451, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28387464

RESUMO

Hydrogen sulphide (H2 S) serves as a vital gastric mucosal defence under acid condition. Non-steroidal anti-inflammatory drugs (NSAIDs) are among widely prescribed medications with effects of antipyresis, analgesia and anti-inflammation. However, their inappropriate use causes gastric lesions and endogenous H2 S deficiency. In this work, we reported the roles of a novel pH-controlled H2 S donor (JK-1) in NSAID-related gastric lesions. We found that JK-1 could release H2 S under mild acidic pH and increase solution pH value. Intragastrical administration of aspirin (ASP), one of NSAIDs, to mice elicited significant gastric lesions, evidenced by mucosal festering and bleeding. It also led to infiltration of inflammatory cells and resultant releases of IL-6 and TNF-α, as well as oxidative injury including myeloperoxidase (MPO) induction and GSH depletion. In addition, the ASP administration statistically inhibited H2 S generation in gastric mucosa, while up-regulated cyclooxygenase (COX)-2 and cystathionine gamma lyase (CSE) expression. Importantly, these adverse effects of ASP were prevented by the intragastrical pre-administration of JK-1. However, JK-1 alone did not markedly alter the property of mouse stomachs. Furthermore, in vitro cellular experiments showed the exposure of gastric mucosal epithelial (GES-1) cells to HClO, imitating MPO-driven oxidative injury, decreased cell viability, increased apoptotic rate and damaged mitochondrial membrane potential, which were reversed by pre-treatment with JK-1. In conclusion, JK-1 was proved to be an acid-sensitive H2 S donor and could attenuate ASP-related gastric lesions through reconstruction of endogenous gastric defence. This work indicates the possible treatment of adverse effects of NSAIDs with pH-controlled H2 S donors in the future.


Assuntos
Aspirina/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Organotiofosfonatos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Cistationina gama-Liase/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Concentração de Íons de Hidrogênio , Interleucina-6/metabolismo , Masculino , Camundongos , Estrutura Molecular , Organotiofosfonatos/química , Organotiofosfonatos/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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