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OBJECTIVE: Intervertebral Disc Degeneration (IVDD) is one of the leading causes of low back pain, significantly impacting both individuals and society. This study aimed to investigate the significance of macrophage infiltration and the role of macrophage-secreted platelet-derived growth factor-BB (PDGF-BB) in IVDD progression. METHODS: To confirm the protective function of macrophage-derived PDGF-BB on nucleus pulposus cells (NPCs), we employed Lysm-Cre transgenic mice to genetically ablate PDGF-B within the myeloid cells. Immunohistochemistry was utilized to detect the expression of glycolytic enzymes and pyroptosis-related proteins during the process of IVDD. Western blot, RT-PCR, ELISA and immunofluorescence were used to detect the protective effect of recombinant PDGF-BB on NPCs. RESULTS: Macrophage-derived PDGF-BB deficiency resulted in the loss of NPCs and the increased ossification of cartilage endplates during lumbar disc degeneration. Also, PDGF-BB deficiency triggered the inhibition of glycolytic enzymes' expression and the activation of pathways related to pyroptosis in the nucleus pulposus. Mechanistically, our results suggest that PDGF-BB predominantly conveys its protective influence on NPCs through the PDGF receptor- beta (PDGFR-ß)/ thioredoxin-interacting protein pathway. CONCLUSIONS: The absence of PDGF-BB originating from macrophages expedites the advancement of IVDD, whereas the application of PDGF-BB treatment holds the potential for retarding intervertebral disc degeneration in the human body.
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Osteoarthritis (OA), a degenerative disease affecting the joint, is characterized by degradation of the joint edge, cartilage injury, and subchondral bone hyperplasia. Treatment of early subchondral bone loss in OA can inhibit subsequent articular degeneration and improve the prognosis of OA. PD0325901, a specific inhibitor of ERK, is widely used in oncology and has potential as a therapeutic agent for osteoarthritis In this study, we investigated the biological function of PD0325901 in bone marrow monocytes/macrophages (BMMs)treated with RANKL and found that it inhibited osteoclast differentiation in vitro in a time- and dose-dependent manner. PD0325901 restrained the expression of osteoclast marker genes, such as c-Fos and NFATc1 induced by RANKL. We tested the biological effects of PD035901 on ATDC5 cells stimulated by IL-1ß and found that it had protective effects on ATDC5 cells. In animal studies, we used a destabilization of the medial meniscus (DMM) model and injected 5 mg/kg or 10 mg/kg of PD0325901 compound into each experimental group of mice. We found that PD0325901 significantly reduced osteochondral pathological changes in post-OA subchondral bone destruction.Finally, we found that PD0325901 down-regulated the pyroptosis level in chondrocytes to rescue cartilage degeneration. Therefore, PD0325901 is expected to be a new generation alternative therapy for OA.
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NF-kappa B , Osteoartrite , Animais , Camundongos , NF-kappa B/metabolismo , Osteoclastos , Transdução de Sinais , Inflamação/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Cartilagem/metabolismo , Cartilagem/patologia , CondrócitosRESUMO
OBJECTIVES: As one of the major causes of low back pain, intervertebral disc degeneration (IDD) has caused a huge problem for humans. Increasing evidence indicates that NLRP3 inflammasome-mediated pyroptosis of NP cells displays an important role in the progression of IDD. Maltol (MA) is a flavoring agent extracted from red ginseng. Due to its anti-inflammatory and antioxidant effects, MA has been widely considered by researchers. Therefore, we hypothesized that MA may be a potential IVD protective agent by regulating NP cells and their surrounding microenvironment. METHODS: In vitro, qRT-PCR, and Western blot were used to explore the effect of MA on the transcription and protein expression of the anabolic protein (ADAMTS5, MMP3, MMP9) catabolic protein (Aggrecan), and pro-inflammatory factor (iNOS COX-2). Next, the effects of MA on PI3K/AKT/NF-κB pathway and pyroptosis pathway were analyzed by Western blot and immunofluorescence. Molecular docking was used to investigate the relationship between PI3K and MA. Moreover, ELISA was also used to detect the effects of MA on inflammatory factors (TNF-α, PGE2, IL-1ß, and IL-18). In vivo, the effects of MA on the vertebral structure of IDD mice were studied by HE and SO staining and the effects of MA on ECM and PI3K/AKT/NF-κB and pyroptosis pathway of IDD mice were studied by immunohistochemical staining. RESULTS: MA can ameliorate intervertebral disc degeneration in vivo and in vitro. Specifically, the molecular docking results showed that the binding degree of MA and PI3K was significant. Second, in vitro studies showed that MA inhibited the degradation of ECM and inflammatory response by inhibiting the PI3K/AKT/NF-κB pathway and the pyroptosis mediated by NLRP3 inflammasome, which increased the expression of anabolic proteins, decreased the expression of catabolic proteins, and decreased the secretion of inflammatory mediators such as IL-18 and IL-1ß. In addition, according to the study results of the mouse lumbar instability model, MA also improved the tissue disorder and degradation of the intervertebral disc, reduced the loss of proteoglycan and glycosaminoglycan, and inhibited intervertebral disc inflammation, indicating that MA has a protective effect on the intervertebral disc to intervertebral disc in mice. CONCLUSIONS: Our results suggest that MA slowed IDD development through the PI3K/AKT/NF-κB signaling pathway and NLRP3 inflammasome-mediated pyroptosis, indicating that MA appeared to be a viable medication for IDD treatment.
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Degeneração do Disco Intervertebral , Núcleo Pulposo , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/metabolismo , Inflamassomos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Piroptose , Simulação de Acoplamento Molecular , Núcleo Pulposo/metabolismoRESUMO
Necroptosis of chondrocytes contributes to the progression of osteoarthritis (OA). Recent studies have shown that VX-11e, an ERK inhibitor, exhibited a contrasting expression pattern to RIP3, the key protein of necroptosis. However, its effect on OA remains to be determined. Therefore, we investigated whether VX-11e affected the loss of articular cartilage and subchondral bone during OA. In in vivo experiments, a mouse OA model induced by medial meniscus instability (destabilization of the medial meniscus [DMM]) was used. In in vitro experiments, interleukin-1ß (IL-1ß) was used to simulate the inflammatory microenvironment of chondrocytes, and RANKL was used to induce osteoclast differentiation. Histological analysis, cell viability experiments, high-density cell culture experiments, immunofluorescence assay, western blot assay, quantitative PCR, and molecular docking experiments were conducted to determine the protective effect of VX-11e on articular cartilage during OA. We also performed histological analysis, tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring formation test, quantitative PCR, and western blot assay to study the effect of VX-11e on subchondral bone during OA progression. We found that after the medial meniscus was severed, the articular cartilage of the mice showed pathological changes, accompanied with the loss of subchondral bone. However, an intraperitoneal injection of VX-11e protected the cartilage and subchondral bone of the mouse knee joint. The results of in vitro experiments showed that VX-11e promoted the anabolism of the extracellular matrix of chondrocytes by inhibiting the expression and phosphorylation of RIP3 and MLKL. VX-11e also inhibited RANKL-induced osteoclast differentiation by inhibiting the ERK/RSK signaling pathway, but not the NF-κB pathway. Overall, VX-11e inhibited the loss of articular cartilage and subchondral bone during OA by regulating the RIP1/RIP3/MLKL and MAPK signaling pathways.
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Cartilagem Articular , Osteoartrite , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Camundongos , Simulação de Acoplamento Molecular , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Proteínas Quinases/farmacologia , Pirimidinas , Pirróis , Transdução de SinaisRESUMO
Osteoarthritis (OA) is a common, age-related, and painful disease characterized by cartilage destruction, osteophyte formation, and synovial hyperplasia. This study revealed that circPDE4D, a circular RNA derived from human linear PDE4D, plays a critical role in maintaining the extracellular cellular matrix (ECM) during OA progression. circPDE4D was significantly downregulated in OA cartilage tissues and during stimulation with inflammatory cytokines. The knockdown of circPDE4D predominantly contributed to Aggrecan loss and the upregulation of matrix catabolic enzymes, including MMP3, MMP13, ADAMTS4, and ADAMTS5, but not proliferation or apoptosis. In a murine model of destabilization of the medial meniscus (DMM), the intraarticular injection of circPDE4D alleviated DMM-induced cartilage impairments. Mechanistically, we found that circPDE4D exerted its effect by acting as a sponge for miR-103a-3p and thereby regulated FGF18 expression, which is a direct target of miR-103a-3p. In conclusion, our findings highlight a novel protective role of circPDE4D in OA pathogenesis and indicate that the targeting of the circPDE4D-miR-103a-3p-FGF18 axis might provide a potential and promising approach for OA therapy.
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Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Fatores de Crescimento de Fibroblastos/genética , MicroRNAs/genética , Osteoartrite/genética , Interferência de RNA , RNA Circular , Biomarcadores , Células Cultivadas , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Osteoartrite/metabolismo , Osteoartrite/patologiaRESUMO
BACKGROUND: Maffucci syndrome (MS) is a rare, nonhereditary congenital mesodermal dysplasia characterized by multiple enchondromas and hemangiomas, associated with an increased risk of developing malignant tumors. Given their rarity, the pathogenesis of these tumors has not been clarified, and there is no standard treatment. CASE PRESENTATION: We present a case of a 45-year-old man with MS to supplement the clinical manifestations and explore the molecular mechanism of MS. The patient underwent amputation surgery to inhibit tumor development and was diagnosed with MS with 1-2 grade giant chondrosarcoma in the left ankle. In addition, the whole exon analysis results revealed isocitrate dehydrogenase 1 (IDH1) R132C mutation in chondrosarcoma lesions but not in blood DNA. CONCLUSIONS: This case report showed MS complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation, which is appropriate to monitor the development of MS pathology and other concomitant lesions.
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Neoplasias Ósseas , Condrossarcoma , Encondromatose , Tornozelo/patologia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/cirurgia , Condrossarcoma/complicações , Condrossarcoma/genética , Condrossarcoma/cirurgia , Encondromatose/complicações , Encondromatose/genética , Encondromatose/cirurgia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: To investigate the effectiveness and feasibility of a novel vertebral osteotomy technique, transpedicular opening-wedge osteotomy (TOWO) was used to correct rigid thoracolumbar kyphotic deformities in patients with ankylosing spondylitis (AS). METHODS: Eighteen AS patients underwent TOWO to correct rigid thoracolumbar kyphosis. Radiographic parameters were compared before surgery, 1 week after surgery and at the last follow-up. The SRS-22 questionnaire was given before surgery and at the last follow-up to evaluate clinical improvement. The operating time, estimated blood loss and complications were analyzed. RESULTS: The mean operating time and estimated blood loss were 236 min and 595 ml, respectively. The mean preoperative sagittal vertical axis (SVA), thoracic kyphosis (TK), pelvic tilt (PT) and thoracolumbar kyphosis (TLK) were 158.97 mm, 51.24 mm, 43.63 mm and 41.74 mm, respectively, and decreased to 66.72 mm, 35.96 mm, 27.21 mm and 8.67 mm at the last follow-up. The mean preoperative lumbar lordosis (LL) and sacral slope (SS) were 8.30 ± 24.43 mm and 19.67 ± 9.40 mm, respectively, which increased to 38.23 mm and 28.13 mm at the last follow-up. The mean height of the anterior column of osteotomized vertebrae increased significantly from 25.17 mm preoperatively to 37.59 mm at the last follow, but the height of the middle column did not change significantly. SRS-22 scores were improved significantly at the last follow-up compared with preoperatively. Solid bone union was achieved in all patients after 12 months of follow-up, and no screw loosening, screw removal or rod breakage was noticed at the last follow-up. CONCLUSIONS: TOWO could achieve satisfactory kyphosis correction by opening the anterior column instead of vertebral body decancellation and posterior column closing, thus simplifying the osteotomy procedure and improving surgical efficacy.
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Cifose , Espondilite Anquilosante , Humanos , Cifose/etiologia , Cifose/cirurgia , Vértebras Lombares/cirurgia , Osteotomia/métodos , Estudos Retrospectivos , Espondilite Anquilosante/complicações , Espondilite Anquilosante/cirurgiaRESUMO
As a serious trauma of the neurological system, spinal cord injury (SCI) results in permanent disability, gives rise to immediate vascular damage and a wide range of matters that induce the breakage of blood spinal cord barrier (BSCB). SCI activates the expression of MMP-2/9, which are considered to accelerate the disruption of BSCB. Recent research shows that Dl-3-n-butylphthalide (NBP) exerted protective effects on blood spinal cord barrier in animals after SCI, but the underlying molecular mechanism of NBP on the BSCB undergoing SCI is unknown. Here, our research show that NBP inhibited the expression of MMP-2/9, then improved the permeability of BSCB following SCI. After the T9 level of spinal cord performed with a moderate injury, NBP was managed by intragastric administration and further performed once a day. NBP remarkably improved the permeability of BSCB and junction proteins degration, then promoted locomotion recovery. The protective effect of NBP on BSCB destruction is related to the regulation of MMP-2/9 induced by SCI. Moreover, NBP obviously inhibited the MMP-2/9 expression and junction proteins degradation in microvascular endothelial cells. In conclusion, our results indicate that MMP-2/9 are relevant to the breakdown of BSCB, NBP impairs BSCB destruction through inhibiting MMP-2/9 and promotes functional recovery subjected to SCI. NBP is likely to become a new nominee as a therapeutic to treat SCI via a transigent BSCB.
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Benzofuranos/uso terapêutico , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Animais , Hipóxia Celular/efeitos dos fármacos , Claudina-5/metabolismo , Feminino , Glucose/deficiência , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Ocludina/metabolismo , Oxigênio/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/enzimologiaRESUMO
PURPOSE: Cerebrospinal fluid leakage (CSFL) is a common complication during spinal surgery. This study aimed to compare dural closure with different suture types, sizes, and techniques, and adhesives to reduce the occurrence of CSFL. MATERIALS AND METHODS: Using a pig spine model, the PDS II 4-0, 5-0, 6-0, Vicryl 4-0, 5-0, 6-0, and Prolene 4-0, 5-0, 6-0 sutures were compared by calculating the permeability after suturing. Spraying bioprotein glue was also tried. Next, 120 patients who underwent surgery for intraspinal subdural tumors were enrolled and received 5-0 PDSII, Vicryl, or Prolene for dura repair. RESULTS: In the animal model study, Vicryl 5-0 showed a reduced leakage flow rate compared with 5-0 Prolene and 5-0 PDS II. In the clinical study, postoperative drainage in the Vicryl group was smaller than that in the other groups during the first 3 days after surgery (p < 0.05). Drainage volume of patients with postoperative cerebrospinal fluid leakage in the Vicryl group was smaller than that in the other groups during the first 3 days after surgery (p < 0.05).There were 12 patients (23.1%, 12/52) in the Vicryl group, 20 patients (55.6%, 20/36) in the PDS group, and 16 patients (50.0%, 16/32) in the Prolene group who had CSFL.The incidence of CSFL was significantly reduced in Vicryl group compared with the other groups(P < 0.05). CONCLUSIONS: 5-0 Vicryl sutures significantly reduced the dural leakage flow rate in an animal spine model. Fibrin glue can reinforce dural repair after surgery. 5-0 Vicryl was associated with a lower occurrence of CSFL in patients.
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Aseptic prosthetic loosening due to wear particle-induced inflammatory osteolysis is the main cause of failure for artificial joint replacement. The inflammatory response and the production of pro-osteoclastic factors lead to elevation of osteoclast formation and excessive activity results in extensive bone destruction around the bone-implant interface. Here we showed that Nepetin, a natural bioactive flavonoid with proven anti-inflammatory and anti-proliferative properties, potently inhibited RANKL-induced osteoclast differentiation, formation and bone resorption in vitro, and protected mice against the deleterious effects of titanium particle-induced calvarial osteolysis in vivo. Mechanistically, Nepetin attenuated RANKL-induced activation of NF-κB and MAPK signalling pathways and TRAF6-dependent ubiquitination of Beclin 1 which is necessary for the induction of autophagy. In brief, our study demonstrates the potential therapeutic application of Nepetin against osteoclast-mediated osteolytic diseases.
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Autofagia/efeitos dos fármacos , Flavonas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Camundongos , Osteólise , Microtomografia por Raio-XRESUMO
Osteoporosis is an ageing disease characterized by elevated osteoclastic bone resorption resulting in bone loss, decrease bone strength, and elevated incidence of fractures. Neferine, a natural compound isolated from the traditional Chinese medicine Nelumbo nucifera (Lotus), has been reported exhibit anti-inflammatory, antioxidant, and anticancer properties. However, its effect on bone remains to be determined. Here we showed that Neferine inhibits RANKL-induced osteoclast formation in a dose- and time-dependent manner. Furthermore, Neferine also demonstrated antiresorptive properties by effectively ameliorating the bone resorptive activity of mature osteoclasts. Mechanistically, Neferine suppressed RANKL-induced activation of NF-κB signaling pathway. This in turn hindered the induction and activation of NFATc1 resulting in downregulation of osteoclast marker genes closely related to differentiation, fusion as well as bone resorption. Interestingly, we found Neferine enhanced the differentiation and bone mineralization activity of MC3T3-E1 preosteoblast cells. Finally, mice treated with Neferine was protected against ovariectomy (OVX)-induced bone loss. The Neferine treatment improved bone volume following ovariectomy and also exhibited less TRAP-positive osteoclasts on bone surface. Collectively our data provide promising evidence that Neferine could be a potential therapeutic application for against osteolytic bone conditions such as osteoporosis.
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Benzilisoquinolinas/farmacologia , Fatores de Transcrição NFATC/genética , Osteogênese/efeitos dos fármacos , Osteoporose/genética , Ligante RANK/genética , Células 3T3 , Animais , Antioxidantes/farmacologia , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , NF-kappa B/genética , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the expression of Toll-like receptor 4 (TLR4)/myeloid differentiation factor (MyD88)/nuclear factor-κB (NF-κB) pathway genes and related inflammatory factors tumor necrosis factor-α (TNF-α), interleukin (IL)-12, IL-6 in patients with secondary spinal cord injury (SSCI) and the correlations with prognosis. METHODS: The clinical data of 105 SSCI patients and 40 healthy subjects were reviewed. According to Frankel's classification of spinal cord injury, the patients were divided into complete injury group and incomplete injury group, and according to the improvement of Japanese Orthopedic Association (JOA) scores, the patients were divided into good prognosis group and poor prognosis group. The expression of TLR4, MyD88, NF-κB in peripheral blood mononuclear cells (PBMC) and serum TNF-α, IL-12, IL-6 levels were compared between SSCI patients and healthy controls, between patients with complete and incomplete injury, between patients with poor and good prognosis. Logistic regression analysis was used to analyze the risk factors leading to poor prognosis of SSCI, and Pearson's correlation analysis was used to analyze the correlation between JOA score and the above indicators. RESULTS: The expressions of TLR4, MyD88, NF-κB in PBMC and serum TNF-α, IL-12, IL-6 levels in SSCI patients were significantly higher than those in healthy subjects (all P<0.01), those in complete injury group were higher than those in incomplete injury group, and those in poor prognosis group were higher than those in good prognosis group (all P<0.01). The proportions of patients with Frankel grade A, spinal cord edema or hemorrhage, spinal cord injury length longer than 4 cm in poor prognosis group was significantly higher than those in good prognosis group (all P<0.01). Logistic regression analysis showed that Frankel grade, spinal cord edema or hemorrhage, length of spinal cord injury, relative expressions of TLR4, MyD88, NF-κB in PBMC, serum levels of TNF-α, IL-12 and IL-6 were risk factors for poor prognosis in SSCI patients (P<0.05 or P<0.01). Pearson's correlation analysis showed that JOA improvement rate was negatively correlated with the relative expressions of TLR4, MyD88, NF-κB mRNA in PBMC and serum TNF-α, IL-12, IL-6 levels (P<0.05 or P<0.01). CONCLUSIONS: The activation of TLR4/MyD88/NF-κB pathway and the up-regulation of the expression of related inflammatory factors TNF-α, IL-12 and IL-6 are involved in the progression of SSCI, which are closely related to the neuroinflammatory injury, and can be used as reference indexes for evaluating prognosis in SSCI patients.
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Fator 88 de Diferenciação Mieloide , NF-kappa B , Traumatismos da Medula Espinal , Receptor 4 Toll-Like , Estudos de Casos e Controles , Humanos , Leucócitos Mononucleares/metabolismo , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Traumatismos da Medula Espinal/fisiopatologia , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
Balanced bone resorption and bone formation are vital for bone homeostasis. Excessive osteoclastic bone resorption in this process can cause a variety of bone disorders including osteoporosis, aseptic prosthetic loosening and tumor associated bone destruction. Bulleyaconitine A (BLA) is a natural compound that has been widely used for pain treatment but its role in osteolysis has not yet been investigated. In this study, we verified for the first time that BLA inhibited osteoclast formation, the mRNA expression of osteoclast-related genes and osteoclastic bone resorption by inhibiting NF-κB signal pathway and downstream NFATc1 expression. Meanwhile, BLA had a stimulatory effect in osteoblast differentiation and mineralization. Furthermore, BLA showed preventive effect in Ti particle-induced osteolysis model in vivo. Together, all our data demonstrated that BLA suppressed osteoclastogenesis and promoted osteoblastogenesis via suppressing NF-κB signal pathway and could be an alternative therapeutic choice against bone loss.
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Aconitina/análogos & derivados , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteólise/induzido quimicamente , Transdução de Sinais , Titânio/efeitos adversos , Aconitina/farmacologia , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteólise/genética , Osteólise/patologia , Ligante RANK/farmacologia , Transdução de Sinais/efeitos dos fármacos , Crânio/patologiaRESUMO
Objective: Ankylosing spondylitis (AS), an autoimmune disease, often leads to lower cervical spine fractures, with the potential for severe spinal nerve damage even from low-energy injuries. The optimal treatment approach remains debated. Methods: A retrospective study involved 17 AS patients with lower cervical spine fractures who received anterior cervical fixation. Most presented cervicothoracic or thoracolumbar kyphosis, with 11 exhibiting neurological deficits. Patient characteristics, clinical data, visual analog scale (VAS), complications, and nerve recovery were analyzed. Results: No postoperative neurological deterioration occurred. All cases experienced complete fusion of fractures during the follow-up period. Preoperative VAS significantly decreased at 3 days and 3 months post-surgery. Of the 11 patients with preoperative neurological deficits, approximately 54.5% showed improvement post-surgery. No complications were reported, such as esophageal fistula, wound infection, or fixation failure. Conclusion: Anterior internal fixation is a possible treatment for AS-related lower cervical fractures. This approach ensures satisfactory spinal stability and neurological recovery with proper cranial traction and external fixation post-surgery. Our findings demonstrate that this surgical method is safe and effective.
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CONTEXT: Concurrent schwannoma and meningioma arising in the high cervical level mimicking a single dumbbell-shaped tumor is significantly rare, most of them were found during the surgeries or postoperative histological findings unexpectedly. The specific feature of schwannoma and meningioma coexistence in high cervical level on MR images has not been clearly described yet. FINDINGS: We presented four cases of concurrent extradural schwannoma and intradural meningioma mimicking a single dumbbell-shaped tumor arising in the high cervical level. There was no interconnection between intradural and extradural masses in any case. In MRI reviews, the signal intensity between intradural lesions and spinal cord was similar on T2 weighted MR images. However, on contrast-enhanced MR images, the intradural lesions were more enhanced than spinal cord and presented as crescent-shaped intradural minor lesions adjacent to the more significantly enhanced extradural major tumor. These MRI findings could not be easily identified without meticulous observation preoperatively. Postoperative pathological findings confirmed the discrete tumors arising in the same cervical level. CONCLUSION: The comparison of signal intensity changes among the spinal cord, intradural tumor and extradural tumor between T2 weighted and contrast-enhanced MR images may be helpful to predict coexistent schwannoma and meningioma in the high cervical level preoperatively. Intradural exploration is highly recommended when less enhanced crescent-shaped intradural minor lesion was observed adjacent to the significantly enhanced dumbbell-shaped major tumor in preoperative MRI findings.
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Neoplasias Epidurais , Neoplasias Meníngeas , Meningioma , Neurilemoma , Traumatismos da Medula Espinal , Neoplasias da Medula Espinal , Humanos , Meningioma/diagnóstico , Meningioma/diagnóstico por imagem , Traumatismos da Medula Espinal/complicações , Neurilemoma/diagnóstico , Neurilemoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias Epidurais/complicações , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/diagnóstico por imagemRESUMO
BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease [1]. It has come to light that AZD8330 can suppress the generation of proinflammatory factors and deter the inflammatory response [2]. Given that inflammation is a primary causative factor in OA, it is posited that AZD8330 might exhibit superior efficacy in OA management. METHODS: In this study, we investigated the potential of intraperitoneal injection of AZD8330 to retard the progression of osteoarthritis in a murine model with surgically induced medial meniscus destruction (DMM). Concurrently, we employed ATDC5 cartilage cells to dissect the mechanism through which AZD8330 inhibits the TNF-α-induced NF-κB signaling pathway via modulation of RIP1. The findings revealed that AZD8330 mitigated cartilage degradation and the inflammatory response, leading to a substantial reduction in OARSI scores among DMM mice treated with AZD8330. Mechanistically, AZD8330 functioned as a suppressor of the TNF-α-induced NF-κB/p65 signaling pathway by facilitating the phosphorylation activation of cIAP1-mediated RIP1. The combination of data from both in vivo and in vitro experiments supports the conclusion that AZD8330 can attenuate chondrocyte degradation, thereby alleviating OA, by regulating the NF-κB/P65 signaling pathway through modulation of RIP1 activity. Consequently, the utilization of AZD8330 may hold potential in the prophylaxis of osteoarthritis. RESULTS: Our investigation delineates the role of AZD8330 in the regulation of inflammation in the context of OA treatment. Furthermore, we have unveiled that the inhibitory impact of AZD8330 on OA may hinge upon the activation of cIAP1, which in turn downregulates RIP1, thereby restraining the NF-κB/P65 signaling pathway. This study lends credence to the notion that AZD8330 may be a promising contender for osteoarthritis therapy. CONCLUSIONS: Our study provides compelling evidence attesting to the capacity of AZD8330 in managing inflammation within the realm of OA treatment. Likewise, our study has elucidated that the attenuation of OA by AZD8330 relies on the activation of cIAP1 to inhibit RIP1, consequently suppressing the NF-κB signaling pathway. On the strength of our present study, we may have identified a viable drug candidate for OA treatment.
Assuntos
NF-kappa B , Osteoartrite , Camundongos , Animais , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Regulação para Cima , Transdução de Sinais , Inflamação/tratamento farmacológico , Condrócitos/metabolismo , Meniscos Tibiais , Necrose/metabolismo , Interleucina-1beta/metabolismoRESUMO
Background: Osteoarthritis (OA), a common chronic joint disease, is characterized by cartilage degeneration and subchondral bone reconstruction. NF-κB signaling pathway-activated inflammation and NLRP3-induced pyroptosis play essential roles in the development of OA. In this study, we examine whether paroxetine can inhibit pyroptosis and reduce osteoclast formation, thereby delaying the destruction of knee joints. Methods: We employed high-density cultures, along with quantitative polymerase chain reactions and Western blotting techniques, to investigate the effects of paroxetine on extracellular matrix synthesis and degradation. The expression levels of NF-κB and pyroptosis-related signaling pathway proteins were examined by Western blotting and immunofluorescence. Furthermore, the impact of paroxetine on RANKL-induced osteoclast formation was evaluated through TRAP staining and F-actin ring fluorescence detection. To investigate the role of paroxetine in vivo, we constructed a mouse model with destabilization of the medial meniscus (DMM) surgery. Safranin O-Fast Green staining, Hematoxylin-Eosin staining, and immunohistochemistry were conducted to observe the extent of knee joint cartilage deformation. In addition, TRAP staining was used to observe the formation of osteoclasts in the subchondral bone. Results: In the in vitro experiments with ATDC5, paroxetine treatment attenuated IL-1ß-induced activation of the pyroptosis-related pathway and suppressed extracellular matrix catabolism by inhibiting the NF-kB signaling pathway. In addition, paroxetine treatment decreased the expression of RANKL-induced osteoclast marker genes and reduced osteoclast formation. In animal experiments conducted in vivo, mice treated with paroxetine exhibited thicker knee cartilage with a smoother surface compared to the DMM group. Additionally, the formation of osteoclasts in the subchondral bone was reduced in the paroxetine-treated mice. Further analysis revealed that paroxetine treatment played a role in preserving the balance of the extracellular matrix and delaying knee joint degeneration. Conclusion: Paroxetine can inhibit pyroptosis and reduce osteoclast formation via inhibiting the NF-κB signaling pathway, suggesting that it may have therapeutic effects in patients with OA.
Assuntos
NF-kappa B , Osteoartrite do Joelho , Animais , Camundongos , Condrócitos , Osteoclastos , Paroxetina/farmacologia , Piroptose , Transdução de SinaisRESUMO
Osteoarthritis (OA) is a disabling joint disease characterized by cartilage degeneration. Reactive oxygen species (ROS)-induced oxidative stress is an important cause of early chondrocyte death. For this reason, we investigated PD184352, a small molecule inhibitor with potential anti-inflammatory and antioxidant activity. We evaluated the protective effect of PD184352 against destabilized medial meniscus (DMM)-induced OA in mice. The knee joints of the PD184352-treated group had higher Nrf2 expression and milder cartilage damage. Moreover, in in vitro experiments, PD184352 suppressed IL-1ß-induced NO, iNOS, PGE2 production, and attenuated pyroptosis. PD184352 treatment promoted antioxidant protein expression and reduced the accumulation of ROS by activating the Nrf2/HO-1 axis. Finally, the anti-inflammatory and antioxidant effects of PD184352 were shown to be partially dependent on Nrf2 activation. Our study reveals the potential role of PD184352 as an antioxidant and provides a new strategy for OA treatment.
Assuntos
Antioxidantes , Osteoartrite , Camundongos , Animais , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Anti-Inflamatórios/uso terapêutico , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Condrócitos , Interleucina-1beta/metabolismoRESUMO
OBJECTIVES: Limonin has received significant attention due to its multiple biological effects, intervertebral disc degeneration (IDD) is also of interest due to the high prevalence of this disease. In this study, we determined the effects of limonin on IDD and the underlying mechanism of action to find novel ways to treat IDD. METHODS: An IL-1ß-induced cell inflammation model and a lumbar instability model inducing IDD were established to assess the progression of IDD with or without limonin treatment. We further evaluated MAPK/NF-κB and necroptosis pathways and alterations in the extracellular matrix specific within the disc. KEY FINDINGS: Limonin suppresses inflammation in the nucleus pulposus in vitro by reducing the production of pro-inflammatory markers such as iNOS and COX-2. Limonin reduced the activation of the MAPK/NF-κB signalling pathway and the RIP1/RIP3/MLKL necroptosis pathway in the NP cells. Moreover, limonin delays the IDD progression in the lumbar instability model. CONCLUSIONS: Limonin could potentially delay IDD by inhibiting NP cell necroptosis and modulating peripheral matrix proteins within the intervertebral disc and is a potential pharmacological research direction for the therapy in patients with IDD.
Assuntos
Degeneração do Disco Intervertebral , Limoninas , Inflamação , Degeneração do Disco Intervertebral/tratamento farmacológico , Limoninas/farmacologia , Limoninas/uso terapêutico , Necroptose , NF-kappa B/metabolismo , Animais , RatosRESUMO
Lung adenocarcinoma is the most common and aggressive type of lung cancer with the highest incidence of bone metastasis. Epidermal growth factor-like domain multiple 6 (EGFL6) is an exocrine protein, and the expression of EGFL6 is correlated with survival of patient with lung adenocarcinoma. However, the association between EGFL6 expression in lung adenocarcinoma and bone metastasis has not been investigated. In this study, we found that EGFL6 levels in lung adenocarcinoma tissues correlate with bone metastasis and TNM stages in surgical patients. In vitro, overexpression of EGFL6 in lung adenocarcinoma cells promoted their proliferation, migration, and invasion ability compared with control by enhancing EMT process and activating Wnt/ß-catenin and PI3K/AKT/mTOR pathways. In the nude mouse model, overexpression of EGFL6 enhanced tumor growth and caused greater bone destruction. Moreover, the exocrine EGFL6 of human lung adenocarcinoma cells increased osteoclast differentiation of bone marrow mononuclear macrophages (BMMs) of mice via the NF-κB and c-Fos/NFATc1 signaling pathways. However, exocrine EGFL6 had no effect on osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs). In conclusion, high expression of EGFL6 in lung adenocarcinomas is associated with bone metastasis in surgical patients. The underlying mechanism may be the increased metastatic properties of lung adenocarcinoma cells with high EGFL6 level and the enhanced osteoclast differentiation and bone resorption by exocrine EGFL6 from tumors. Therefore, EGFL6 is a potential therapeutic target to reduce the ability of lung adenocarcinomas to grow and metastasize and to preserve bone mass in patients with bone metastases from lung adenocarcinomas.