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BACKGROUND: Diagnosing chronic periprosthetic joint infection (PJI) is challenging. No single biomarker can accurately recognize PJI preoperatively in a timely manner. Therefore, the aim of the present study was to investigate the usefulness of the serum neutrophil-to-lymphocyte ratio (NLR) in aiding the diagnosis of chronic PJI. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 158 patients who had undergone revision arthroplasty (104 with aseptic mechanic failure and 54 with chronic PJI) from July 2011 to July 2020. Univariate analysis followed by multivariate logistic regression was applied to compare NLR, C-reactive protein (CRP), and erythrocyte sedimentation ratio (ESR) between the two groups. The receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of NLR alone and in combination with CRP and ESR. RESULTS: NLR, CRP, and ESR were significantly higher in patients with chronic PJI than in the aseptic revision group (p < 0.05). ROC curve analysis revealed that NLR had a sensitivity of 57.41% and a specificity of 77.88% with an optimal threshold of 2.56. The optimal threshold for CRP and ESR was 7.00 mg/L (sensitivity 62.50% and specificity 83.12%) and 43 mm/h (sensitivity 59.38% and specificity 80.52%), respectively. The combined diagnostic value of NLR with CRP and ESR was shown to have no additional diagnostic value in predicting chronic PJI. CONCLUSION: Compared with traditional inflammatory biomarkers (ESR and CRP), the value of serum NLR alone or combined with CRP and ESR for diagnosing chronic PJI is limited. LEVEL OF EVIDENCE: Level 3.
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Artroplastia de Quadril , Infecções Relacionadas à Prótese , Biomarcadores , Humanos , Linfócitos , Neutrófilos , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/cirurgia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Aseptic prosthesis loosening (APL) is one of the most prevalent complications associated with arthroplasty. The main cause is the periprosthetic osteolysis induced by wear particles. However, the specific mechanisms of crosstalk between immune cells and osteoclasts/osteoblasts during osteolysis are unclear. In this study, we report the role and mechanism of macrophage-derived exosomes in wear particle-induced osteolysis. The results of exosomes up-taken experiments revealed that osteoblast and mature osteoclasts capture macrophage-derived exosomes (M-Exo). Next-generation sequencing and RT-qPCR on M-Exo revealed that exosomal microRNA miR-3470b was downregulated in wear particle-induced osteolysis. The results of analysis on Luciferase reporter assays/fluorescence in situ hybridization (FISH)/immunofluorescence (IF)/immunohistochemistry (IHC) and co-culture experiments demonstrated that wear particles induced osteoclast differentiation by increasing the expression of NFatc1 via M-Exo miR-3470b targeting TAB3/ NF-κB signaling. We also illustrate that engineered exosomes enriching miR-3470b facilitated to suppressed the osteolysis; the microenvironment enriching with miR-3470b could suppress wear particle-induced osteolysis via inhibition of TAB3/ NF-κB in vivo. In summary, our findings indicate that macrophage-derived exosomes transfer to osteoclasts to induce osteolysis in wear particle-induced APL. Engineering exosomes enriching with miR-3470b might be a novel strategy for the targeting treatment of bone resorption-related diseases.
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Aseptic loosening caused by peri-implant osteolysis (PIO) is a common complication after joint replacement, and there is still no better treatment than revision surgery. The wear particle-induced inflammation response, especially subsequent osteoclastic bone resorption, is responsible for PIO. As the importance of wear particles in inducing autophagy in cells around the prosthesis in PIO has been discovered, this might be a central process underlying aseptic loosening. However, the role of autophagy induced by wear particles in osteoclastogenesis during PIO remains unclear. In this study, we investigated the role of autophagy in osteoclastogenesis and verified it in a mouse calvarial osteolysis model. We found that osteoclasts were increased in the interface membranes of patients with aseptic loosening. In vitro, knocking down the Atg5 gene or using autophagy inhibitors (3-MA, LY294002) to inhibit autophagy was found to repress osteoclastogenesis and decrease expression of the osteoclast-related genes TRAP, cathepsin K, and matrix metalloprotein 9 (MMP-9) with or without titanium (Ti) particles. In vivo, 3-MA and LY294002 repressed Ti particle-stimulated osteolysis and osteoclastogenesis and reduced expression of the pro-inflammatory factors TNF-α, IL-1ß, and IL-6. Our results suggest that 3-MA and LY294002 might be the potential medicines to prevent and treat PIO and aseptic loosening.
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Osteólise , Animais , Autofagia , Cromonas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas , Osteoclastos , Osteogênese , Osteólise/induzido quimicamente , Titânio/efeitos adversosRESUMO
OBJECTIVES: To investigate abnormally methylated-differentially expressed genes (DEGs) and their related pathways in osteoarthritis (OA) by comprehensive bioinformatic analysis. METHODS: Gene expression profiles of GSE51588 and GSE114007, and a gene methylation microarray data GSE63695 were downloaded from the Gene Expression Omnibus (GEO) repository. Abnormally methylated DEGs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of these genes were subsequently performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The protein-protein interaction (PPI) network was built from STRING. Module analysis and hub gene identification were performed by using Cytoscape. Co-expression analysis was also constructed using the CEMiTool package. RESULTS: In total, 133 abnormally methylated DEGs were identified, including 85 hypomethylation high-expression genes and 48 hypermethylation low-expression genes. Among biological processes and KEGG pathways of abnormally methylated DEGs, collagen fibril organization was enriched most frequently, and pathways of oxidative stress and aging were enriched, including HIF-1 signaling pathway, AMPK signaling pathway, and FoxO signaling pathway. In PPI networks, the hub genes of hypomethylation high-expression genes were COL1A1, COL3A1, COL1A2, COL5A2, LUM, MMP2, SPARC, COL2A1, COL6A2, and COL7A1, and the hub genes of hypermethylation low-expression genes were VEGFA, SLC2A1, LDHA, PDK1, and BNIP3. Combined with co-expression analysis, COL3A1, LUM, and MMP2 were the critical hypomethylation high-expression hub genes in medial tibia subchondral bone. CONCLUSIONS: Our study implied abnormally methylated DEGs and dysregulated pathways in OA. Common methylation biomarkers included COL3A1, LUM, and MMP2, and we also found that THBS2 may serve as a novel biomarker in end-stage OA. Key Points ⢠Abnormally methylated differentially expressed genes regulate osteoarthritis. ⢠Hypomethylation high-expression genes were related to the extracellular matrix. ⢠Hypermethylation low-expression genes were related to oxidative stress and aging. ⢠COL3A1, LUM, and MMP2 were potential methylation biomarkers for osteoarthritis.
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Biologia Computacional , Osteoartrite , Metilação de DNA , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Osteoartrite/genéticaRESUMO
Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown. Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC. Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1. Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening.
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BACKGROUND: Perioperative hyperglycemia is a risk factor for postoperative complications after total joint arthroplasty (TJA). However, the variability of fasting blood glucose (FBG) after TJA remains unknown. We aimed to assess the fluctuation and extent of elevation of FBG following primary or revision TJA. METHODS: We retrospectively evaluated the medical records of 1788 patients who underwent primary or revision TJA between 2013 and 2018. We examined FBG values collected during 6 days of the perioperative period. The findings for each time point were evaluated with descriptive statistics. Postoperative glycemic variability was assessed by the coefficient of variation (CV). RESULTS: The final cohort included the medical records of 1480 patients (1417 primary and 63 revision). FBG was highest on postoperative day 1 in the primary and revision groups (P < 0.001), which had the highest number of hyperglycemic patients (FBG > 100 mg/dL), with 66.4% and 75.5% in the primary and revision groups, respectively. The CV of diabetics in the primary group, and diabetics and non-diabetics in the revision group, was higher than that of non-diabetics in the primary group. CONCLUSION: Postoperative day 1 showed the highest FBG levels and proportion of patients with hyperglycemia in the perioperative period. Primary group diabetics, and revision group diabetics and non-diabetics, had higher postoperative fluctuation of FBG than primary group non-diabetics. Frequent FBG monitoring may therefore be warranted in diabetic patients undergoing TJA, and all patients undergoing revision TJA.
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Artroplastia de Quadril , Artroplastia do Joelho , Glicemia/metabolismo , Jejum/sangue , Hiperglicemia/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Idoso , Biomarcadores/sangue , Feminino , Humanos , Hiperglicemia/complicações , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Período Pós-Operatório , Reoperação , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Periprosthetic joint infection (PJI) has been increasingly documented; however, its preoperative accurate diagnosis remains challenging. Furthermore, there is a dire need to identify appropriate and effective biomarkers. We aimed to evaluate the relationship between globulin, albumin to globulin (A/G) ratio, and development of PJI in patients undergoing revision total joint arthroplasty (TJA). METHODS: A retrospective study was conducted on patients who had undergone revision TJA between 2011 and 2018 (89 with aseptic mechanic failure and 38 with PJI). The serum proteins were explored using univariate analysis followed by multivariate logistic regression. The diagnostic performance of these proteins was assessed by the receiver operating characteristic (ROC) curve. RESULTS: Higher globulin levels (odds ratio [OR], 1.239; P < 0.001) and lower A/G ratio (OR, 0.007; P < 0.001) were strongly associated with the risk of PJI. ROC curve analysis demonstrated reasonable diagnostic performance for globulin (area under the curve [AUC], 0.77; sensitivity, 78.95%; and specificity, 69.66%) and A/G ratio (AUC, 0.779; sensitivity, 65.79%; and specificity, 78.65%). CONCLUSIONS: Both globulin and A/G ratio were associated with PJI and may serve as potential adjuvant biomarkers in the diagnosis of PJI.
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Artroplastia de Substituição/efeitos adversos , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/etiologia , Albumina Sérica/análise , Soroglobulinas/análise , Idoso , Biomarcadores/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reoperação , Estudos RetrospectivosRESUMO
Chronic inflammation and infection in the tissue surrounding implants after total joint replacement is closely associated with the innate immune response to surgical implants. Wear particles are known to increase apoptosis and impair the innate immunity in macrophages, which can cause immunosuppression around the implants. Excessive autophagy can induce apoptosis. However, the link between autophagy and apoptosis in macrophages during chronic inflammation and infection remains unknown. In this study, we investigated the autophagy and apoptosis induced by titanium particles in RAW264.7 macrophages, and in the interface membrane of patients with late-onset periprosthetic joint infection (PJI). We found that titanium particles stimulated autophagy and apoptosis in macrophages. Inhibition of autophagy significantly reduced titanium particle-induced apoptosis in macrophages, which may be related to the PI3K/Akt signaling pathway. The secretion of inflammatory factors, such as IL-1ß, IL-6, and TNF-α, decreased after inhibition of autophagy in titanium particle-stimulated macrophages, which may be caused by immune dysfunction due to titanium particle-induced autophagy and apoptosis in macrophages. Furthermore, our in vivo mouse calvarial model also showed that autophagy inhibitors lowered the rate of cell apoptosis. Our findings indicate that wear particle-induced apoptosis may be caused by enhanced autophagy in macrophages, which could potentially impair the local innate immunity in periprosthetic tissues and could be a risk factor for PJI. Based on these results, autophagy modulators may act as a new therapeutic option for PJI.
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Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/efeitos adversos , Macrófagos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Titânio/efeitos adversos , Animais , Autofagia/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Fosfatidilinositol 3-Quinases/imunologia , Próteses e Implantes/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/imunologia , Células RAW 264.7RESUMO
Macrophages play an essential role in inflammation. Protein disulfide isomerase (PDI) is central to the redox system, which is closely linked with the inflammatory function of macrophages. However, the relationship between PDI and inflammation is still unknown. In this study, we tested the effects of PDI on inflammatory responses in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS). Using CRISPR/Cas9 system, we found that PDI knockout suppressed migration, M1 polarization, and secretion of tumor necrosis factor-α (TNF-α) and interluekin-6 (IL-6). The repression of these inflammatory processes was accompanied by decreased production of reactive oxygen species (ROS). PDI ablation also inactivated the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activated the phosphorylation of NF-κB inhibitor alpha (IκBα). These findings demonstrate that PDI knockout inhibits the inflammatory function of macrophages by decreasing ROS production and inactivating NF-κB pathway.
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Inflamação/genética , Macrófagos/imunologia , NF-kappa B/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Técnicas de Inativação de Genes , Camundongos , Oxirredução , Fosforilação , Células RAW 264.7 , Transdução de SinaisRESUMO
Aseptic implant loosening is a devastating long-term complication of total joint arthroplasty. It is mainly initiated by the interaction of wear debris and macrophages. However, how does the chronic inflammation persist and how to stop it is poorly understood. Sphingosine kinases (SPHKs) are an essential feature of immunosuppressive M2 polarisation in macrophages and a promoter for chronic inflammation. In this study, RAW 264.7 macrophages were exposed to stimulation with titanium particles (0.1 mg/ml), and the subsequent expression of SPHKs and pro-inflammatory cytokines was evaluated. The effect of inhibitors of SPHKs (FTY720, PF543, and ABC294640) on titanium particle-challenged macrophages was analysed. As for results, the amount of sphingosine kinase (SPHK)-1 and SPHK-2 in RAW264.7 macrophages increased in the presence of titanium particles in a time-dependent manner. Two inhibitors of SPHKs (FTY720 and ABC294640) suppressed titanium particle-induced tumour necrosis factor (TNF)-α and interleukin (IL)-6 production in RAW264.7 macrophages. These findings suggest that persistent stimulation with titanium particles may lead to a consistent release of TNF-α and IL-6 via SPHK-2 activity, which may lead to aseptic implant loosening. Appropriate regulation of SPHK-2 may serve as a potential new strategy in the treatment of aseptic implant loosening.