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Scientific Reports May 2024Recently, we found significantly reduced total superoxide dismutase (SOD) activity in the cartilage of patients with end-stage knee osteoarthritis (OA). In this study,...
Recently, we found significantly reduced total superoxide dismutase (SOD) activity in the cartilage of patients with end-stage knee osteoarthritis (OA). In this study, we aimed to evaluate the SOD activity in serum, joint fluid, cartilage, and synovial membrane samples collected from 52 patients with end-stage knee OA who underwent total knee arthroplasty. The relationship between the total SOD activity in each tissue was evaluated using Spearman's rank correlation coefficient. The joint fluid total SOD activity was used as the objective variable, and its association with the serum, cartilage, and synovial total SOD activities was evaluated using multiple linear regression analysis. Univariate analysis revealed that joint fluid total SOD activity was positively correlated with synovial total SOD activity. Multiple linear regression analysis using joint fluid total SOD activity as the objective variable showed a positive association with synovial total SOD activity (β = 0.493, adjusted R = 0.172, P < 0.01). In patients with end-stage knee OA, the state of the synovial total SOD activity is better reflected by the total SOD activity in the joint fluid than that in the cartilage. Joint fluid total SOD activity may serve as a biomarker for the treatment and prevention of synovitis.
Topics: Humans; Osteoarthritis, Knee; Male; Female; Synovial Fluid; Superoxide Dismutase; Synovial Membrane; Aged; Middle Aged; Biomarkers; Cartilage, Articular; Arthroplasty, Replacement, Knee
PubMed: 38802533
DOI: 10.1038/s41598-024-62614-x -
Frontiers in Immunology 2024Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key... (Review)
Review
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA.
Topics: Humans; Arthritis, Rheumatoid; Macrophages; Signal Transduction; Synovial Membrane; Fibroblasts; Animals; Macrophage Activation; Cell Communication; Metabolic Reprogramming
PubMed: 38799455
DOI: 10.3389/fimmu.2024.1394108 -
Frontiers in Immunology 2024levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. can be produced by Th17 cells and locally within joints by tissue-resident...
OBJECTIVES
levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. can be produced by Th17 cells and locally within joints by tissue-resident cells. induces osteoblast mineralization . As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of in spondyloarthritis.
METHODS
Serum, peripheral blood mononuclear cells ( = 15-35) and synovial tissue ( = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR.
RESULTS
Synovial tissue of axSpA patients shows significantly more -positive cells than that of HCs ( < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs ( < 0.001 and < 0.01). However, peripheral blood CD4 T cells from axSpA and PsA patients show higher positivity for in the PrimeFlow assay compared with HCs. CD4 memory T cells from axSpA patients produce more under Th17-favoring conditions (IL-1β and IL-23) than cells from PsA and RA patients or HCs.
CONCLUSION
production is increased in the synovial tissue of SpA and can be localized to CD68 macrophage-like synoviocytes, whereas circulating Th17 cells are only modestly enriched. Considering the osteoproliferative properties of , this offers new therapeutic options independent of Th17 pathways.
Topics: Humans; Arthritis, Psoriatic; Synoviocytes; Male; Adult; Female; Antigens, CD; Interleukins; Middle Aged; Antigens, Differentiation, Myelomonocytic; Axial Spondyloarthritis; Th17 Cells; Synovial Membrane; Joints; Arthritis, Rheumatoid
PubMed: 38799447
DOI: 10.3389/fimmu.2024.1355824 -
Pharmaceuticals (Basel, Switzerland) May 2024Rheumatoid arthritis (RA) is a complex illness with both hereditary and environmental components. Globally, in 2019, 18 million people had RA. RA is characterized by... (Review)
Review
Rheumatoid arthritis (RA) is a complex illness with both hereditary and environmental components. Globally, in 2019, 18 million people had RA. RA is characterized by persistent inflammation of the synovial membrane that lines the joints, cartilage loss, and bone erosion. Phenolic molecules are the most prevalent secondary metabolites in plants, with a diverse spectrum of biological actions that benefit functional meals and nutraceuticals. These compounds have received a lot of attention recently because they have antioxidant, anti-inflammatory, immunomodulatory, and anti-rheumatoid activity by modulating tumor necrosis factor, mitogen-activated protein kinase, nuclear factor kappa-light-chain-enhancer of activated B cells, and c-Jun N-terminal kinases, as well as other preventative properties. This article discusses dietary polyphenols, their pharmacological properties, and innovative delivery technologies for the treatment of RA, with a focus on their possible biological activities. Nonetheless, commercialization of polyphenols may be achievable only after confirming their safety profile and completing successful clinical trials.
PubMed: 38794160
DOI: 10.3390/ph17050590 -
Medicina (Kaunas, Lithuania) Apr 2024(1) : Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial...
(1) : Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial myofibroblasts, implicated in synovial fibrosis and OA-related pain, offer a potential explanation for these sex differences. Additionally, interleukin-24 (IL24), known for its role in autoimmune disorders and potential myofibroblast production, adds complexity to understanding sex-specific variations in OA. We investigate its role in OA and its contribution to observed sex differences. (2) : To assess gender-specific variations, we analyzed myofibroblast marker expression and levels in synovial tissue samples from propensity-matched male and female OA patients (each = 34). Gene expression was quantified using quantitative polymerase chain reaction (qPCR). The association between expression levels and pain severity, measured by a visual analog scale (VAS), was examined to understand the link between and OA pain. Synovial fibroblast subsets, including CD45-CD31-CD39- (fibroblast) and CD45-CD31-CD39+ (myofibroblast), were magnetically isolated from female patients ( = 5), and expression was compared between these subsets. (3) : Females exhibited significantly higher expression of myofibroblast markers (MYH11, ET1, ENTPD2) and compared to males. expression positively correlated with pain severity in females, while no correlation was observed in males. Further exploration revealed that the myofibroblast fraction highly expressed compared to the fibroblast fraction in both male and female samples. There was no difference in the myofibroblast fraction between males and females. (4) : Our study highlights the gender-specific role of myofibroblasts and IL24 in OA pathogenesis. Elevated IL24 levels in females, correlating with pain severity, suggest its involvement in OA pain experiences. The potential therapeutic implications of IL24, demonstrated in autoimmune disorders, open avenues for targeted interventions. Notwithstanding the limitations of the study, our findings contribute to understanding OA's multifaceted nature and advocate for future research exploring mechanistic underpinnings and clinical applications of IL24 in synovial myofibroblasts. Additionally, future research directions should focus on elucidating the precise mechanisms by which IL24 contributes to OA pathology and exploring its potential as a therapeutic target for personalized medicine approaches.
Topics: Humans; Female; Male; Myofibroblasts; Interleukins; Synovial Membrane; Osteoarthritis; Middle Aged; Aged; Propensity Score; Sex Factors; Pain
PubMed: 38792924
DOI: 10.3390/medicina60050741 -
Frontiers in Pharmacology 2024Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the synovial joint, which leads to inflammation, loss of function, joint destruction,... (Review)
Review
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the synovial joint, which leads to inflammation, loss of function, joint destruction, and disability. The disease biology of RA involves complex interactions between genetic and environmental factors and is strongly associated with various immune cells, and each of the cell types contributes differently to disease pathogenesis. Several immunomodulatory molecules, such as cytokines, are secreted from the immune cells and intervene in the pathogenesis of RA. In immune cells, membrane proteins such as ion channels and transporters mediate the transport of charged ions to regulate intracellular signaling pathways. Ion channels control the membrane potential and effector functions such as cytotoxic activity. Moreover, clinical studies investigating patients with mutations and alterations in ion channels and transporters revealed their importance in effective immune responses. Recent studies have shown that voltage-gated potassium channels and calcium-activated potassium channels and their subtypes are involved in the regulation of immune cells and RA. Due to the role of these channels in the pathogenesis of RA and from multiple pieces of clinical evidence, they can be considered therapeutic targets for the treatment of RA. Here, we describe the role of voltage-gated and calcium-activated potassium channels and their subtypes in RA and their pharmacological application as drug targets.
PubMed: 38783950
DOI: 10.3389/fphar.2024.1286069 -
Analytica Chimica Acta Nov 2023Total joint arthroplasty (TJA) has significantly improved the quality of life for millions suffering from end-stage arthritis. However, periprosthetic joint infections...
BACKGROUND
Total joint arthroplasty (TJA) has significantly improved the quality of life for millions suffering from end-stage arthritis. However, periprosthetic joint infections (PJI) remain a serious complication, necessitating extensive interventions and prolonged antimicrobial treatments. The aging population is expected to lead to a rise in TJA cases, subsequently increasing the incidence of PJI, particularly in the elderly who face higher mortality rates. Current diagnostic methods for suspected PJI, such as radiographs and biochemical markers like CRP and ESR, exhibit limited sensitivity. Therefore, there is a critical need for a specific synovial fluid biomarker assay to enhance PJI diagnosis using specific SF-based assay.
RESULTS
This study introduces a novel microfluidic chip with a paper-based aptamer-sandwich assay for the quantitative detection of HNP 1, a crucial PJI biomarker, in synovial fluid. The assay leverages the advantages of aptamers over antibodies, demonstrating high selectivity and affinity for target molecules. The integration of a nitrocellulose (NC) membrane onto the microfluidic platform represents a significant advancement, reducing background signals and simplifying the assay procedure without intricate procedure and pre-treatment. The NC membrane-based microfluidic device offers rapid, cost-effective, and highly sensitive detection of HNP 1, with a limit of detection of 0.5 mg L. The microfluidic device demonstrates exceptional performance, detecting up to four clinical samples in approximately 42 min on a single chip with 100 % accuracy, as confirmed by analysis of 12 clinical samples and comparison with "gold-standard". Moreover, the assay exhibits a wide dynamic range of 0.5-100 mg L-1, underscoring its potential as a powerful tool for PJI diagnosis in clinical settings.
SIGNIFICANCE
This work introduces a paper-based microfluidic system tailored for rapid HNP 1 detection using synovial fluid near joint region (and not serum via blood) for better diagnosis. The innovative paper-based aptamer-sandwich assay yields results within 42-min. Significantly, it boasts a wide dynamic range, detecting levels from an impressive 0.5 mg L-1, crucial in the 2.6 mg L-1 threshold region. This heightened sensitivity and expansive detection capability establish our assay as a leader in PJI diagnostics, promising unmatched precision and efficiency in clinical applications.
Topics: Humans; Aptamers, Nucleotide; Biomarkers; Lab-On-A-Chip Devices; Limit of Detection; Microfluidic Analytical Techniques; Paper; Prosthesis-Related Infections; Synovial Fluid; alpha-Defensins
PubMed: 38783735
DOI: 10.1016/j.aca.2023.341879 -
Arthritis Research & Therapy May 2024Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid... (Review)
Review
Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid arthritis (RA). FLSs are emerging as promising new therapeutic targets in RA. However, fibroblasts perform many essential functions that are required for sustaining tissue homeostasis. Direct targeting of general fibroblast markers on FLSs is challenging because fibroblasts in other tissues might be altered and side effects such as reduced wound healing or fibrosis can occur. To date, no FLS-specific targeted therapies have been applied in the clinical management of RA. With the help of high-throughput technologies such as scRNA-seq in recent years, several specific pathogenic FLS subsets in RA have been identified. Understanding the characteristics of these pathogenic FLS clusters and the mechanisms that drive their differentiation can provide new insights into the development of novel FLS-targeting strategies for RA. Here, we discuss the pathogenic FLS subsets in RA that have been elucidated in recent years and potential strategies for targeting pathogenic FLSs.
Topics: Arthritis, Rheumatoid; Humans; Fibroblasts; Synoviocytes; Synovial Membrane; Animals; Cell Differentiation
PubMed: 38783357
DOI: 10.1186/s13075-024-03343-4 -
Scientific Reports May 2024Knee osteoarthritis (OA) diagnosis is based on symptoms, assessed through questionnaires such as the WOMAC. However, the inconsistency of pain recording and the...
Characterization of clinical data for patient stratification in moderate osteoarthritis with support vector machines, regulatory network models, and verification against osteoarthritis Initiative data.
Knee osteoarthritis (OA) diagnosis is based on symptoms, assessed through questionnaires such as the WOMAC. However, the inconsistency of pain recording and the discrepancy between joint phenotype and symptoms highlight the need for objective biomarkers in knee OA diagnosis. To this end, we study relationships among clinical and molecular data in a cohort of women (n = 51) with Kellgren-Lawrence grade 2-3 knee OA through a Support Vector Machine (SVM) and a regulation network model. Clinical descriptors (i.e., pain catastrophism, depression, functionality, joint pain, rigidity, sensitization and synovitis) are used to classify patients. A Youden's test is performed for each classifier to determine optimal binarization thresholds for the descriptors. Thresholds are tested against patient stratification according to baseline WOMAC data from the Osteoarthritis Initiative, and the mean accuracy is 0.97. For our cohort, the data used as SVM inputs are knee OA descriptors, synovial fluid proteomic measurements (n = 25), and transcription factor activation obtained from regulatory network model stimulated with the synovial fluid measurements. The relative weights after classification reflect input importance. The performance of each classifier is evaluated through ROC-AUC analysis. The best classifier with clinical data is pain catastrophism (AUC = 0.9), highly influenced by funcionality and pain sensetization, suggesting that kinesophobia is involved in pain perception. With synovial fluid proteins used as input, leptin strongly influences every classifier, suggesting the importance of low-grade inflammation. When transcription factors are used, the mean AUC is limited to 0.608, which can be related to the pleomorphic behaviour of osteoarthritic chondrocytes. Nevertheless, funcionality has an AUC of 0.7 with a decisive importance of FOXO downregulation. Though larger and longitudinal cohorts are needed, this unique combination of SVM and regulatory network model shall help to stratify knee OA patients more objectively.
Topics: Humans; Female; Osteoarthritis, Knee; Support Vector Machine; Middle Aged; Aged; Gene Regulatory Networks; Biomarkers; Synovial Fluid; Proteomics
PubMed: 38782951
DOI: 10.1038/s41598-024-62212-x -
Frontiers in Immunology 2024
Topics: Arthritis, Rheumatoid; Humans; Fibroblasts; Synoviocytes; Immunomodulation; Animals; Synovial Membrane
PubMed: 38779670
DOI: 10.3389/fimmu.2024.1415672