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Experimental & Molecular Medicine Apr 2024Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that...
Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that orosomucoid-2 (ORM2), an acute phase reactant, was differentially expressed in rheumatoid arthritis (RA) patients and showed the highest fold change. Therefore, we questioned the extent to which ORM2, which is produced mainly in the liver, actively participates in rheumatoid inflammation. Surprisingly, ORM2 expression was upregulated in the synovial fluids and synovial membranes of RA patients. The major cell types producing ORM2 were synovial macrophages and fibroblast-like synoviocytes (FLSs) from RA patients. Recombinant ORM2 robustly increased IL-6, TNF-α, CXCL8 (IL-8), and CCL2 production by RA macrophages and FLSs via the NF-κB and p38 MAPK pathways. Interestingly, glycophorin C, a membrane protein for determining erythrocyte shape, was the receptor for ORM2. Intra-articular injection of ORM2 increased the severity of arthritis in mice and accelerated the infiltration of macrophages into the affected joints. Moreover, circulating ORM2 levels correlated with RA activity and radiographic progression. In conclusion, the acute phase protein ORM2 can directly increase the production of proinflammatory mediators and promote chronic arthritis in mice, suggesting that ORM2 could be a new therapeutic target for RA.
Topics: Arthritis, Rheumatoid; Humans; Animals; Orosomucoid; Mice; Macrophages; Male; Female; Synovial Membrane; Acute-Phase Proteins; Synoviocytes; Cytokines; Middle Aged; Synovial Fluid; Inflammation; Biomarkers; Inflammation Mediators; Disease Models, Animal
PubMed: 38556552
DOI: 10.1038/s12276-024-01188-0 -
Communications Biology Mar 2024Osteoarthritis (OA) is one of the leading causes of disability, affecting over 500 million adults worldwide. Previous studies have found that various inflammatory...
Osteoarthritis (OA) is one of the leading causes of disability, affecting over 500 million adults worldwide. Previous studies have found that various inflammatory factors can contribute to the pathogenesis of OA, including complement factors in the synovial fluid of OA patients. However, the pathogenesis of this disease is still not known, and the only therapy of severe OA is total joint replacements. Total joint replacements are invasive, expensive, and affect quality of life. Here we show that when human articular chondrocytes are stimulated with pro-inflammatory mediator interleukin-1β (IL-1β) there is an increase in inflammatory factors including complement component 3 (C3). We also found the transcription factor, signal transducer and activator of transcription 1 (STAT1), is responsible for increased C3 expression after IL-1β stimulation in human articular chondrocytes. A specific STAT1 inhibitor, fludarabine, attenuates the hyper-expression of C3 and delays/prevents spontaneous OA in Dunkin-Hartley guinea pigs. Since fludarabine is already clinically used for chemotherapy, this study has great translational potential as a unique disease-modifying osteoarthritis drug (DMOAD) in treating primary OA.
Topics: Adult; Humans; Guinea Pigs; Animals; Complement C3; Quality of Life; Osteoarthritis; Interleukin-1beta; Synovial Fluid; STAT1 Transcription Factor
PubMed: 38538870
DOI: 10.1038/s42003-024-06051-6 -
Arthritis Research & Therapy Mar 2024Peptidoglycan (PG) is an arthritogenic bacterial cell wall component whose role in human osteoarthritis is poorly understood. The purpose of this study was to determine...
OBJECTIVES
Peptidoglycan (PG) is an arthritogenic bacterial cell wall component whose role in human osteoarthritis is poorly understood. The purpose of this study was to determine if PG is present in synovial tissue of osteoarthritis patients at the time of primary total knee arthroplasty (TKA), and if its presence is associated with inflammation and patient reported outcomes.
METHODS
Intraoperative synovial tissue and synovial fluid samples were obtained from 56 patients undergoing primary TKA, none of whom had history of infection. PG in synovial tissue was detected by immunohistochemistry (IHC) and immunofluorescence microscopy (IFM). Synovial tissue inflammation and fibrosis were assessed by histopathology and synovial fluid cytokine quantification. Primary human fibroblasts isolated from arthritis synovial tissue were stimulated with PG to determine inflammatory cytokine response.
RESULTS
A total of 33/56 (59%) of primary TKA synovial tissue samples were positive for PG by IHC, and PG staining colocalized with markers of synovial macrophages and fibroblasts by IFM. Synovial tissue inflammation and elevated IL-6 in synovial fluid positively correlated with PG positivity. Primary human fibroblasts stimulated with PG secreted high levels of IL-6, consistent with ex vivo findings. Interestingly, we observed a significant inverse correlation between PG and age at time of TKA, indicating younger age at time of TKA was associated with higher PG levels.
CONCLUSION
Peptidoglycan is commonly found in synovial tissue from patients undergoing TKA. Our data indicate that PG may play an important role in inflammatory synovitis, particularly in patients who undergo TKA at a relatively younger age.
Topics: Humans; Peptidoglycan; Interleukin-6; Synovial Membrane; Osteoarthritis; Synovial Fluid; Cytokines; Inflammation; Cell Wall
PubMed: 38532447
DOI: 10.1186/s13075-024-03293-x -
Frontiers in Immunology 2024Temporomandibular joint (TMJ) osteoarthritis (OA) is a common TMJ degenerative disease with an unclear mechanism. Synovial fluid (SF), an important component of TMJ,...
INTRODUCTION
Temporomandibular joint (TMJ) osteoarthritis (OA) is a common TMJ degenerative disease with an unclear mechanism. Synovial fluid (SF), an important component of TMJ, contains various proteins and metabolites that may directly contribute to OA. The present study aimed to investigate the influence of SF in TMJOA at the metabolite level.
METHODS
Untargeted and widely targeted metabolic profiling were employed to identify metabolic changes in SF of 90 patients with different TMJOA grades according to TMJ magnetic resonance imaging.
RESULTS
A total 1498 metabolites were detected. Most of the metabolites were amino acids and associated metabolites, benzene and substituted derivatives, and lipids. Among patients with mild, moderate and severe TMJOA, 164 gradually increasing and 176 gradually decreasing metabolites were identified, indicating that biosynthesis of cofactors, choline metabolism, mineral absorption and selenocompound metabolism are closely related to TMJOA grade. Combined metabolomics and clinical examination revealed 37 upregulated metabolites and 16 downregulated metabolites in patients with pain, of which 19 and 26 metabolites were positively and negatively correlated, respectively, with maximum interincisal opening. A model was constructed to diagnose TMJOA grade and nine biomarkers were identified. The identified metabolites are key to exploring the mechanism of TMJOA.
DISCUSSION
In the present study, a metabolic profile was constructed and assessed using a much larger number of human SF samples from patients with TMJOA, and a model was established to contribute to the diagnosis of TMJOA grade. The findings expand our knowledge of metabolites in human SF of TMJOA patients, and provide an important basis for further research on the pathogenesis and treatment of TMJOA.
Topics: Humans; Synovial Fluid; Temporomandibular Joint; Osteoarthritis; Temporomandibular Joint Disorders; Metabolomics
PubMed: 38529278
DOI: 10.3389/fimmu.2024.1335181 -
American Journal of Veterinary Research Jun 2024Polyacrylamide hydrogel (4% PAHG) is an inert viscoelastic supplement used to manage osteoarthritis in horses. Even with a prolonged clinical effect, horses may be...
OBJECTIVE
Polyacrylamide hydrogel (4% PAHG) is an inert viscoelastic supplement used to manage osteoarthritis in horses. Even with a prolonged clinical effect, horses may be administered multiple doses during their performance career. The effect of the serial 4% PAHG treatments is not known. The objectives of this study were to evaluate the clinical, histologic, and synovial fluid biomarker effects following serial administration of 4% PAHG in normal equine fetlock joints.
ANIMALS
8 healthy horses.
METHODS
In a blinded, controlled in vivo study, horses received serial intra-articular injections of 4% PAHG (Noltrex Vet; Nucleus ProVets LLC) and contralateral 0.9% saline control on days 0, 45, 90, and 135. Treatment and control joints were randomly assigned. Synovial fluid was collected before administration of 4% PAHG or 0.9% saline on day 0 and at study completion for cellular and biomarker evaluation. Serial physical and lameness examinations were performed throughout the study. On day 240, gross examination and harvest of cartilage and synovial membrane for histology were completed.
RESULTS
There were no histologic changes in articular cartilage or synovial fluid biomarkers. The 4% PAHG was seen on the surface of the synovium in 5 of 8 treated joints 105 days after the last treatment. There are minimal effects following serial injections of 4% PAHG on normal joints in horses following administration at 0, 45, 90, and 135 days, with final evaluation on day 240.
CLINICAL RELEVANCE
Serial administration of intra-articular 4% PAHG in horses may provide long-term joint lubrication with no detrimental effects.
Topics: Animals; Horses; Synovial Fluid; Acrylic Resins; Injections, Intra-Articular; Biomarkers; Female; Male; Horse Diseases; Lameness, Animal; Synovial Membrane; Cartilage, Articular; Osteoarthritis; Joints
PubMed: 38513345
DOI: 10.2460/ajvr.24.01.0016 -
PloS One 2024The tribological behaviour of articular cartilage plays a key role in joint motion; however, there is a gap in research on the effect of hyperuricemic joint fluid on...
The tribological behaviour of articular cartilage plays a key role in joint motion; however, there is a gap in research on the effect of hyperuricemic joint fluid on cartilage friction behaviour in acute gouty arthritis. In this study, we carried out a fixed-load scratch experiment to compare the friction and wear of articular cartilage under the lubrication of gouty arthritis arthritic fluid and normal human arthritic fluid, and the results showed that the cartilage friction coefficient of patients with acute gouty arthritis was significantly larger than that of normal human beings, and that the cartilage friction coefficient decreased with the elevation of normal load and sliding speed, and the change with the sliding speed varied more differently from that of normal human beings, and that the cartilage surface wear was more severe after prolonged friction. The wear and tear of the cartilage surface is more severe after prolonged friction. Patients with gouty arthritis should reduce the sudden speed changes such as fast running and variable speed running to maintain the stability of the cartilage surface friction coefficient.
Topics: Humans; Cartilage, Articular; Friction; Arthritis, Gouty; Stress, Mechanical; Synovial Fluid; Lubrication
PubMed: 38512881
DOI: 10.1371/journal.pone.0298722 -
Arthritis Research & Therapy Mar 2024Pain from osteoarthritis (OA) is one of the top causes of disability worldwide, but effective treatment is lacking. Nociceptive factors are released by activated...
BACKGROUND
Pain from osteoarthritis (OA) is one of the top causes of disability worldwide, but effective treatment is lacking. Nociceptive factors are released by activated synovial macrophages in OA, but depletion of synovial macrophages paradoxically worsens inflammation and tissue damage in previous studies. Rather than depleting macrophages, we hypothesized that inhibiting macrophage activation may improve pain without increasing tissue damage. We aimed to identify key mechanisms mediating synovial macrophage activation and test the role of STAT signaling in macrophages on pain outcomes in experimental knee OA.
METHODS
We induced experimental knee OA in rats via knee destabilization surgery, and performed RNA sequencing analysis on sorted synovial tissue macrophages to identify macrophage activation mechanisms. Liposomes laden with STAT1 or STAT6 inhibitors, vehicle (control), or clodronate (depletion control) were delivered selectively to synovial macrophages via serial intra-articular injections up to 12 weeks after OA induction. Treatment effects on knee and hindpaw mechanical pain sensitivity were measured during OA development, along with synovitis, cartilage damage, and synovial macrophage infiltration using histopathology and immunofluorescence. Lastly, crosstalk between drug-treated synovial tissue and articular chondrocytes was assessed in co-culture.
RESULTS
The majority of pathways identified by transcriptomic analyses in OA synovial macrophages involve STAT signaling. As expected, macrophage depletion reduced pain, but increased synovial tissue fibrosis and vascularization. In contrast, STAT6 inhibition in macrophages led to marked, sustained improvements in mechanical pain sensitivity and synovial inflammation without worsening synovial or cartilage pathology. During co-culture, STAT6 inhibitor-treated synovial tissue had minimal effects on healthy chondrocyte gene expression, whereas STAT1 inhibitor-treated synovium induced changes in numerous cartilage turnover-related genes.
CONCLUSION
These results suggest that STAT signaling is a major mediator of synovial macrophage activation in experimental knee OA. STAT6 may be a key mechanism mediating the release of nociceptive factors from macrophages and the development of mechanical pain sensitivity. Whereas therapeutic depletion of macrophages paradoxically increases inflammation and fibrosis, blocking STAT6-mediated synovial macrophage activation may be a novel strategy for OA-pain management without accelerating tissue damage.
Topics: Animals; Rats; Fibrosis; Inflammation; Macrophage Activation; Osteoarthritis, Knee; Pain; Synovial Membrane; STAT6 Transcription Factor
PubMed: 38509602
DOI: 10.1186/s13075-024-03309-6 -
Journal of Applied Biomedicine Mar 2024Endoplasmic reticulum (ER) stress has been shown to play an important role in osteoarthritis (OA).
Endoplasmic reticulum stress-related protein GRP78 and CHOP levels in synovial fluid correlate with disease progression of primary knee osteoarthritis: A cross-sectional study.
BACKGROUND
Endoplasmic reticulum (ER) stress has been shown to play an important role in osteoarthritis (OA).
OBJECTIVE
This study was aimed at assessing the relationship of endoplasmic reticulum (ER) stress-related glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) concentrations in the serum/synovial fluid (SF) with disease severity of primary knee osteoarthritis (pkOA).
METHODS
Patients with pkOA together with healthy individuals were consecutively recruited from our hospital. The levels of GRP78 and CHOP in serum / SF were detected using enzyme-linked immunosorbent assay. The levels of IL-6 and MMP-3 were also examined. Radiographic progression of pkOA was evaluated based on Kellgren-Lawrence (K-L) grades. Receiver Operating Characteristic (ROC) curves were used to assess the diagnostic value of GRP78/CHOP levels with regard to K-L grades. The assessment of clinical severity was conducted using the visual analogue scale (VAS), Oxford knee score (OKS), and Lequesne algofunctional index (LAI).
RESULTS
A total of 140 pkOA patients and 140 healthy individuals were included. Serum GRP78 and CHOP levels in pkOA patients were not significantly different from those in healthy individuals. The SF GRP78 and CHOP levels in healthy controls were not detected due to ethical reasons. Compared to those with K-L grade 2 and 3, the pkOA patients with K-L grade 4 had higher GRP78 and CHOP levels in the SF with statistical significance. In addition, the pkOA patients with K-L grade 3 exhibited drastically upregulated GRP78 and CHOP concentrations in the SF compared to those with K-L grade 2. Positive correlations of GRP78 and CHOP levels with K-L grades, IL-6, and MMP-3 levels in the SF were observed. ROC curve analysis indicated that both GRP78 and CHOP levels may act as decent indicators with regard to OA. GRP78 and CHOP concentrations in the SF were positively correlated with VAS/LAI score and negatively associated with OKS score.
CONCLUSION
The study indicated that GRP78 and CHOP levels in the SF but not the serum were positively correlated with disease severity of pkOA.
Topics: Humans; Osteoarthritis, Knee; Synovial Fluid; Matrix Metalloproteinase 3; Cross-Sectional Studies; Endoplasmic Reticulum Chaperone BiP; Interleukin-6; Biomarkers; Disease Progression
PubMed: 38505969
DOI: 10.32725/jab.2024.001 -
International Immunopharmacology Apr 2024Previous study has indicated that Celastrol (Cel) has various physiological and pharmacological effects, including antibacterial, antioxidant, pro-apoptotic, anticancer...
Previous study has indicated that Celastrol (Cel) has various physiological and pharmacological effects, including antibacterial, antioxidant, pro-apoptotic, anticancer and anti-rheumatoid arthritis (RA) effects. However, low water solubility, low oral bioavailability, narrow treatment window, and high incidence of systemic adverse reactions still limit the further clinical application of Cel. Here, aiming at effectively overcome those shortcomings of Cel to boost its beneficial effects for treating RA, we developed the leukosome (LEUKO) coated biomimetic nanoparticles (NPs) for the targeted delivery of Cel to arthritis injury area in RA. LEUKO were synthesized using membrane proteins purified from activated J774 macrophage. LEUKO and Cel-loaded LEUKO (Cel@LEUKO) were characterized using dynamic light scattering and transmission electron microscopy. Our results demonstrated that Cel@LEUKO can inhibit the inflammatory response of lipopolysaccharide (LPS) induced mouse monocyte macrophage leukemia cells (RAW264.7 cells) and human rheumatoid arthritis synovial fibroblasts (MH7A) cells through the inhibition of reactive oxygen species (ROS)-NF-κB pathway. In addition, research has shown that LEUKO effectively targets and transports Cel to the inflammatory site of RA, increased drug concentration in affected areas, reduced systemic toxicity of Cel, and reduced clinical symptoms, inflammatory infiltration, bone erosion, and serum inflammatory factors in collagen-induced arthritis (CIA) rats.
Topics: Mice; Rats; Humans; Animals; NF-kappa B; Inflammasomes; Reactive Oxygen Species; Biomimetics; Arthritis, Rheumatoid; Nanoparticles; Arthritis, Experimental; Pentacyclic Triterpenes
PubMed: 38503010
DOI: 10.1016/j.intimp.2024.111822 -
Reumatologia Clinica Mar 2024Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Adenosine deaminase (ADA) activity has shown good performance in diagnosing pleural, peritoneal, and meningeal tuberculosis. This meta-analysis aimed to evaluate the performance of measuring ADA activity in synovial fluid for the early diagnosis of joint tuberculosis.
METHODS
We searched published information in MEDLINE, Embase, Cochrane Library, Web of Science, and MedRxiv databases, as well as unpublished information in the American College of Rheumatology and European League Against Rheumatism for conference abstracts (2012-2021). We also scanned the reference lists of articles. Two reviewers independently applied the criteria for selection, assessed quality, and extracted data (PROSPERO number CRD42021284472).
RESULTS
Seven independent studies (N=305 subjects) that compared ADA activity in synovial fluid with a composite reference diagnostic method for tuberculosis were included. Overall, the risk of bias was judged low. Studies were classified as high quality (n=3; 148 subjects) and low quality (n=4; 157 subjects). Pooled sensitivity and specificity of ADA activity was 94% (95% confidence interval [CI], 0.89-98; I=23%) and 88% (95% CI, 83-92; I=83%), respectively. The random-effects model for pooled diagnostic Odds ratio was 67.1 (95%CI, 20.3-222.2; I=30%). The receiver operating characteristic curve area was 0.96 (95% CI, 0.92-0.99). Meta-regression did not identify the quality of the study, country of publication, or the type of assay as a source of heterogeneity.
CONCLUSIONS
Measuring ADA activity in synovial fluid demonstrates good performance for the early diagnosis of joint tuberculosis.
Topics: Humans; Adenosine Deaminase; Synovial Fluid; Sensitivity and Specificity; Tuberculosis, Osteoarticular; Arthritis
PubMed: 38494302
DOI: 10.1016/j.reumae.2024.02.002