Synovial Levels Research Articles

Effects of Repeated Exposure to Ambient Cold on the Development of Inflammatory Pain in a Rat Model of Knee Arthritis

This study investigated the effects of ambient cold exposure on inflammatory pain development, synovial cytokine levels, and spinal cord glial cell activation. Male Sprague–Dawley rats (6 weeks old) were divided into Cold and RT groups. The Cold group was exposed to cold (4 ± 1 °C) for 6 h/day for 5 consecutive days, while the RT group remained at room temperature (22 ± 1 °C). On day 6, knee arthritis was induced via intra-articular carrageenan injection. Pain was assessed by weight-bearing forces (WBFs) of the affected limb. Synovial pro-inflammatory (IL-1 β, IL-6, and TNF-α) and anti-inflammatory (IL-10) cytokines were measured by ELISA, while spinal cord microglia and astrocytes activation were evaluated via immunohistochemistry. WBFs were maximally reduced 4 h post-carrageenan injection, gradually recovering afterward. Cold-exposed rats showed significantly decreased WBF on days 1 and 2 post-injection compared to the RT group. In the Cold group, synovial cytokines (IL-1β, IL-6, IL-10) were significantly elevated 4 h post-injection, with no change in TNF-α levels. Additionally, OX42-positive cells (microglia) significantly increased 1 h post-injection in the Cold group, while GFAP-positive cells (astrocyte) remained unchanged. Repeated ambient cold exposure enhances inflammatory pain development through the regulation of synovial cytokines and microglia activation in the spinal cord in carrageenan-induced knee arthritis.

Application of superb microvascular imaging technology in clinical disease activity of rheumatoid arthritis.

Detection of synovitis is essential for assessing the activity and predicting the prognosis of rheumatoid arthritis (RA). The aim of this study was to investigate the diagnostic performance of superb microvascular imaging (SMI) in RA patients with high, moderate, and low activity. One hundred four patients with active RA were selected from the hospital between May 2022 and August 2023. The study observed the correlation between bone erosion of the carpal joint, joint cavity effusion, thickness of synovial hyperplasia of the carpal joint, positivity rate of synovial blood vessels, and their semiquantitative scores with the clinical disease activity of RA using SMI examination. The detection of synovial hyperplasia thickness and joint effusion in the high-activity group was higher than that in the low-activity group, and the difference was statistically significant (P < 0.05). The quantitative SMI test demonstrated that the synovial blood flow grading and semiquantitative grade increased gradually with activity level (P<0.05). During the high, moderate, and low-activity groups, the vascular index (VI) value of the hyperplastic synovial membrane decreased gradually, showing statistical significance both between and within the groups (P<0.05). SMI technology exhibited high sensitivity and accuracy in assessing disease activity in RA. It holds significant clinical application value as a reliable auxiliary tool for assessing disease activity in RA and treatment. Key Points • Super micro-vascular imaging (SMI) demonstrated higher detection rates of microvesselsin RA patients with high disease activity compared to those with low activity, showing statistical significance. • The quantitative SMI test revealed a clear correlation between synovial blood flow grading and disease activity levels in RA patients, highlighting the potential of SMI as a valuable tool for disease activity and treatment of rheumatoid arthritis.

The Role of Adipokines between Genders in the Pathogenesis of Osteoarthritis

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability—in particular, between genders. Recent research has increasingly focused on the role of adipokines—especially leptin, adiponectin, and resistin—in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin’s role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease.

A-281 Comparison of C-reactive Protein, Procalcitonin, and Presepsin in Blood and Synovial Fluid as Diagnostic Biomarkers for Septic Arthritis

Abstract Background Early detection and prompt treatment are crucial for managing septic arthritis (SA). However, diagnosing SA at an early stage can be challenging since the symptoms are non-specific, and there is no definitive diagnostic test available. This study aimed to investigate the potential of biomarkers as a reliable diagnostic tool for SA. Methods A prospective study was conducted to collect residual blood and synovial fluid samples from patients who underwent blood sampling and arthrocentesis for differential diagnosis due to suspected SA. The collected samples were analyzed for C-reactive protein (CRP), procalcitonin, and presepsin. The data obtained from the analysis were subjected to statistical analysis. Results From January to November 2023, 58 patients were enrolled. They comprised 24 men and 34 women with a median age of 71.1 (interquartile range, IQR 64.0-79.3) years. Twenty-one patients were diagnosed with SA and 37 with non-SA, including osteoarthritis (n=2), osteonecrosis (n=1), meniscus tear (n=1), abscess (n=1), contusion (n=2), and mechanical complications of implants (n=30). There were no significant differences in age or sex distribution between the two groups. The median blood and synovial fluid CRP levels were 4.24 and 1.85 mg/dL, respectively, in the SA group and 0.24 and 0.11 in the non-SA group. The median blood and synovial fluid procalcitonin levels were 0.0383 and 0.0403 ng/mL in the SA group and 0.0358 and 0.0488 in the non-SA group. The median blood and synovial fluid presepsin levels were 307 and 1389 pg/mL in the SA group and 192 and 959 in the non-SA group. Except for blood procalcitonin, all showed statistically significant differences between the SA and non-SA groups. In the ROC curve analysis, blood CRP displayed the highest area under the curve (AUC) of 0.795 with a 0.47 mg/dL cut-off value, 90.5% sensitivity, and 64.9% specificity. Synovial fluid CRP displayed similar results of 0.786 AUC, 0.30 mg/dL cut-off value, 85.0% sensitivity, and 71.4% specificity. Blood and synovial fluid procalcitonin had low AUCs of 0.532 and 0.659, respectively, and were insufficient to differentiate between SA and NS groups. The AUC (0.696 vs. 0.704), sensitivity (76.2% vs. 76.2%), and specificity (67.6% vs. 62.2%) of blood and synovial fluid presepsin were similar; however, synovial fluid showed a significantly higher cut-off value, 4.5 times that of blood (237 pg/mL vs. 1087 pg/mL). Conclusions Procalcitonin was not a reliable marker for distinguishing between SA and non-SA, regardless of whether it was measured in blood or synovial fluids. However, CRP and presepsin proved useful markers when measured in either blood or synovial fluid. In particular, when measuring presepsin in synovial fluid, an optimal cut-off value is needed.

Association of serum and synovial adipokines (chemerin and resistin) with inflammatory markers and ultrasonographic evaluation scores in patients with knee joint osteoarthritis- a pilot study.

Chemerin and resistin are adipokines studied as potential markers for early diagnosis and disease severity in patients with knee osteoarthritis (KOA) Therefore, we aimed to investigate the associations serum and synovial levels of chemerin and resistin with inflammatory parameters and ultrasonographic scores (US) in KOA individuals. Serum was collected from 28 patients with KOA and synovial fluid was obtained from 16 of them. Another 31 age and sex matched cases with no joint disease were included as healthy controls. Concentrations of chemerin, resistin, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were determined with ELISA. Erythrocyte sedimentation rate (ESR), C-reactive protein, serum uric acid (UA) were measured in the patients group. Participants with KOA underwent US assessment using the Outcome Measures in Rheumatology (OMERACT) scores. Patients with KOA had statistically significant higher level of serum resistin than healthy controls [11.05 (3.78-24.13) ng/mL and 7.23 (3.83-12.19) respectively, p < 0.001]. A strong correlation was found between serum chemerin and ESR (r = 0.434, p = 0.021), uric acid (r = 0.573, p = 0.001) as well as the US (r=-0.872, p < 0.001). Serum resistin demonstrated significant association with TNF-alpha (r = 0.398, p = 0.044). In conclusion, both chemerin and resistin might contribute to inflammatory changes associated with KOA. Further studies are needed to elucidate their potential role in the pathogenesis of the disease.

Effect of moxibustion on plasma amino acid metabolism in rats with knee osteoarthritis.

To observe the effect of moxibustion at "Zusanli "(ST36) on the plasma amino acid metabolism in rats with knee osteoarthritis (KOA), and to explore the amino acid metabolism mechanism of moxibustion in repairing cartilage injury in KOA. A total of 30 SD rats were randomly divided into normal, model and moxibustion groups, with 10 rats in each group. Rats in the model and moxibustion groups were injected with the mixture of L-cysteine and papain into bilateral knee joint cavity to make the KOA model. The moxibustion group received moxibustion at bilateral ST36 for 30 min, once daily for 30 days. At the end of the experiment, the swelling degree of knee joint was calculated, the mechanical pain threshold was measured by the Von Frey filament, the cartilage tissue injury was observed by HE staining, the matrix metalloproteinase-13 (MMP-13) content in the synovial tissue was detected by enzyme-linked immunosorbent assay (ELISA), and the differential amino acid metabolites in plasma were detected and screened by liquid chromatography-mass spectrometry (LC-MS). Compared with the normal group, the model group showed irregular cartilage surface, decreased number of chondrocytes, uneven distribution, and local clusters of chondrocytes；the contour of the tide line was blurred. The degree of joint swelling in the model group was higher than that in the normal group (P<0.01), the mechanical pain threshold was lower (P<0.01), and the content of MMP-13 in synovial tissue was higher (P<0.01). The contents of proline and tryptophan in the model group were down-regulated (P<0.01, P<0.05). Compared with the model group, the cartilage tissue damage and knee joint swelling were decreased(P<0.05), mechanical pain threshold was increased(P<0.05), MMP-13 content in synovial tissue and levels of glutamate and histidine expression were decreased (P<0.01, P<0.05). Moxibustion at ST36 significantly alleviated arthritis-related swelling and pain in KOA model rats, attenuated cartilage damage, and regulated levels of certain plasma amino acid metabolites. Moxibustion may regulate KOA cartilage synthesis and degradation through amino acid metabolic pathways such as proline, tryptophan, glutamate and histidine, exerting anti-inflammatory, analgesic, and protection of cartilage injury effects.

Platelet lysate does not have an anti-inflammatory effect on monoiodoacetic acid-induced equine persistent synovitis.

To clarify the anti-inflammatory effect of platelet lysate (PL) on equine persistent synovitis by using a model of synovitis induced by monoiodoacetic acid (MIA). Nonseptic synovitis was induced by administering MIA into both antebrachiocarpal joints of 6 clinically healthy horses on day 0. On days 23, 30, and 37, carpal circumference measurement and synovial fluid collection for assays (leucocytes, LDH, tumor necrosis factor-α, and TGF-β1) were performed, after which PL was injected into 1 antebrachiocarpal joint and saline into the contralateral joint. Synovium and synovial fluid were obtained on day 44 for histological analysis and quantification of inflammation-related genes (matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs 4, receptor activator of nuclear factor κ-Β ligand, and collagen type I α2 chain) and the abovementioned proteins. The LDH level on day 44 was significantly lower in the PL-injected joint than in the saline-treated one. However, no significant differences were found in the other indices quantified, including osteoclast counts on the synovium. Multiple IA administration of PL does not exert anti-inflammatory effects on the equine persistent synovitis induced by MIA. Intra-articular PL administration did not alter many inflammatory biomarkers, suggesting that PL does not have a direct anti-inflammatory effect. However, the reduction in synovial LDH levels suggests that PL promoted joint tissue repair and may consequently alleviate inflammation at the site of administration.

Cell-specific gene networks and drivers in rheumatoid arthritis synovial tissues.

Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18 (fibroblast-like synoviocyte), 16 (T cells), 19 (B cells) and 11 (monocyte) key regulators in RA synovial tissues. Interestingly, fibroblast-like synoviocyte (FLS) and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of Natural killer T (NKT) cells and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected Key driver genes (KDG), TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.

Unveiling the Pathophysiology of Osteoarthritis in Joint Anatomy

Background: Osteoarthritis (OA) is a prevalent and debilitating joint disorder characterized by the degeneration of articular cartilage and underlying bone. Understanding the pathophysiology of OA is essential for developing targeted therapies and improving patient outcomes. Objective: To explore the underlying pathophysiological mechanisms of osteoarthritis within the context of joint anatomy, focusing on cartilage degradation, synovial inflammation, and subchondral bone changes. Methods: This prospective study was conducted at private hospitals in Karachi from June 2022 to December 2022. Eighty patients aged 45 to 70 years, diagnosed with OA, were included. Detailed clinical evaluations were performed, including pain assessment using the Visual Analog Scale (VAS) and functional status assessment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Radiographic analysis was conducted using the Kellgren-Lawrence grading scale. Biochemical analysis of serum and synovial fluid was performed to measure levels of collagen type II cleavage products (C2C), cartilage oligomeric matrix protein (COMP), and inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Synovial fluid and tissue samples were collected during arthroscopy or joint replacement surgery for molecular pathway analysis. Data were analyzed using SPSS version 25, with correlations and regression analyses performed to identify predictors of disease progression. Results: OA was associated with significant pain and functional impairment, with a mean pain score of 7.2 ± 1.3 on the VAS and WOMAC scores averaging 55 ± 10 for physical function and 30 ± 5 for stiffness. Radiographic analysis showed 25% of patients classified as grade II, 50% as grade III, and 25% as grade IV. Biochemical markers indicated elevated levels of C2C (serum: 150 ± 20 ng/mL; synovial fluid: 200 ± 25 ng/mL) and COMP (serum: 10 ± 2 µg/mL; synovial fluid: 15 ± 3 µg/mL). Inflammatory cytokines were also elevated (IL-1β: 50 ± 5 pg/mL; TNF-α: 75 ± 10 pg/mL; IL-6: 100 ± 12 pg/mL). A strong positive correlation (r = 0.85, p &lt; 0.01) was observed between VAS pain scores and synovial IL-1β levels. Conclusion: The pathophysiology of osteoarthritis involves a complex interplay of biomechanical, biochemical, and cellular factors. The findings from this study enhance the understanding of OA mechanisms and provide a foundation for developing more effective therapeutic strategies aimed at halting or reversing the progression of OA.

Quantitative proteomic analysis of circulating exosomes reveals the mechanism by which Triptolide protects against collagen-induced arthritis.

Triptolide (TP), a natural product derived from the herbal medicine Tripterygium wilfordii, exhibits potent immunosuppressive activity. However, the mechanisms underlying its effects in rheumatoid arthritisremain incompletely understood. Collagen-induced arthritis (CIA) model was induced in Sprague-Dawley rats by immunization with bovine type II collagen, and TP was administrated as treatment. The therapeutic effect of TP was evaluated based on paw swelling, histopathology, and serum levels of inflammatory factors. Exosomes isolated from rat serum were characterized by transmission electron microscopy, dynamic light scattering, and western blotanalysis. Proteomic profiling of exosomes was analyzed by direct DIA quantitative proteomics analysis. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes databases were employed for enrichment analysis related to molecular function, biological processes, and signaling pathways. Western blot analysis was used to analyze differentially expressed proteins. TP treatment ameliorated arthritic phenotypes in CIA rats as evidenced by reduced arthritis score, paw swelling, pathological injury severity scores, and serum levels of inflammatory cytokines. The proteomic analysis revealed that TP treatment significantly inhibited complement and coagulation cascades, interleukin-17 signaling pathway, and cholesterol metabolism, which were reactivated in CIA rats. Importantly, lipocalin 2 (LCN2) and myeloperoxidase (MPO) levels were markedly upregulated in the CIA group but suppressed upon TP administration. Furthermore, in synovial tissues, LCN2 and MPO expression levels were also elevated in the CIA group but decreased following TP treatment. Our findings demonstrate that TP alleviates CIA, possibly through modulation of exosomal LCN2 and MPO proteins.

The Effects Of Surgical Arthroscopy And Intraarticular Medication On The Antioxidant System And Lipid Peroxidation In Knee Osteoarthritis

&lt;b&gt;Aim: &lt;/b&gt;This study aims to evaluate the effects of joint surgery through arthroscopy, intraarticular medication, and antioxidant therapy on the antioxidant system and lipid peroxidation in patients with knee osteoarthritis (KOA). The study examines the ability of high-molecular weight hyaluronan, sodium hyaluronate, and oral Vitamin E to modulate oxidative stress markers in the knee joint.&lt;br /&gt; &lt;b&gt;Methods and Materials: &lt;/b&gt;There were 60 patients diagnosed with KOA that were divided into four groups according to the type of treatment for this prospective study at the Department of Orthopaedics and Traumatology. Blood and synovial fluid samples collected before and after treatment were evaluated for superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), lipid peroxidation (malondialdehyde, MDA) catalase (CAT). SPSS software was used to perform statistical analysis where the significance level was set at p&amp;lt;0.05.&lt;br /&gt; &lt;b&gt;Results: &lt;/b&gt;Synovial fluid malondialdehyde levels that showed a decreased tendency among treated groups indicated a reduced state of antioxidant activity. However, no significant changes were observed in systemic oxidative stress markers. These findings show that localized antioxidant therapy within the knee can be effective in reducing oxidative stress, therefore, may have implications for nonsurgical treatment of KOA.&lt;br /&gt; &lt;b&gt;Conclusion: &lt;/b&gt;The results emphasize possible gains made from combining surgical arthroscopy together with antioxidant treatment in managing KOA. By reducing the level of oxidative stress within the knee joint, this combined method can provide a viable solution to improve symptoms and quality of life among KOA patients.

Synovial osteoclastogenesis mediated by chondrocyte-secreted TNFα promotes TMJ condylar resorption.

Insufficient occlusal support (IOS) frequently causes subchondral bone absorption in temporomandibular joint osteoarthritis, and the underlying mechanism requires further investigation. An IOS model was established by abrading rat molars. Micro-computed tomography was used to evaluate subchondral bone changes. Osteoclastogenesis of synovium-derived macrophages (SDMs) was confirmed by TRAP staining. Cartilage-specific TNFα depletion was achieved by intra-articular injection of adeno-associated virus carrying shRNA against murine TNFα under control of collagen type II. Invitro, chondrocytes were mechanically compressed and conditioned medium (CM) was collected to detect its ability to induce osteoclastogenesis of SDMs. Synovial osteoclastogenesis and condyle resorption were observed following IOS. TNFα level was elevated in hypertrophic chondrocytes after IOS. Synovial Wnt5a level increased, but Wnt3a level decreased after IOS. Depletion of TNFα in chondrocytes alleviated the synovial osteoclastogenesis and condyle bone resorption. Invitro compression of chondrocytes potentiated TNFα expression and secretion. The CM promoted osteoclastogenesis of SDMs, which were partially prohibited by TNFα neutralizing antibody. Furthermore, inhibition of Wnt3a facilitated osteoclastogenesis, whereas inhibition of Wnt5a partially suppressed osteoclastogenesis, of SDMs cultured in CM. Chondrocyte-secreted TNFα induced by IOS is a critical regulator of synovial osteoclastogenesis and subsequent condylar resorption, partially through non-canonical Wnt5a pathway.

Interleukin-1β Polymorphisms Are Genetic Markers of Susceptibility to Periprosthetic Joint Infection in Total Hip and Knee Arthroplasty.

Periprosthetic joint infections (PJIs) are serious complications of prosthetic surgery. The criteria for the diagnosis of PJI integrate clinical and laboratory findings in a complex and sometimes inconclusive workflow. Host immune factors hold potential as diagnostic biomarkers in bone and joint infections. We reported that the humoral pattern-recognition molecule long pentraxin 3 (PTX3) predicts PJI in total hip and knee arthroplasty (THA and TKA, respectively). If and how genetic variation in PTX3 and inflammatory genes that affect its expression (IL-1β, IL-6, IL-10, and IL-17A) contributes to the risk of PJI is unknown. We conducted a case-control study on a Caucasian historic cohort of THA and TKA patients who had prosthesis explant due to PJI (cases) or aseptic complications (controls). Saliva was collected from 93 subjects and used to extract DNA and genotype PTX3, IL-1β, IL-6, IL-10, and IL-17A single-nucleotide polymorphisms (SNPs). Moreover, the concentration of IL-1β, IL-10, and IL-6 was measured in synovial fluid and plasma. No association was found between PTX3 polymorphisms and PJI; however, the AGG haplotype, encompassing rs2853550, rs1143634, and rs1143627 in IL-1β, was linked to the infection (p = 0.017). Also, synovial levels of all inflammatory markers were higher in cases than in controls, and a correlation emerged between synovial concentration of PTX3 and that of IL-1β in cases only (Spearman r = 0.67, p = 0.004). We identified a relationship between rs2853550 and the synovial concentration of IL-1β and PTX3. Our findings suggest that IL-1β SNPs could be used for the early identification of THA and TKA patients with a high risk of infection.

Bacterial peptidoglycan drives synovial inflammation in osteoarthritis

Abstract Peptidoglycan (PG) is a potent inflammatory mediator. We have previously demonstrated that PG is present in the synovial tissue of osteoarthritis (OA) patients but its role in OA inflammation remains unknown. We hypothesized that PG in synovial tissue drives inflammation in OA. Intraoperative synovial tissue and synovial fluid samples were obtained from 56 consecutive patients with OA, with no prior history of infection. PG in synovial tissue was detected by immunohistochemical (IHC) staining of serial sections of 10 mm2 of tissue with anti-PG antiserum. PG was found in 33/56 (59%) of the tissue samples using IHC, with a median of eight PG occurrences per 10 mm2 in PG-positive samples. Tissue inflammation and fibrosis were assessed by histopathology. Cellular localization was further characterized in three PG-positive tissue samples by immunofluorescent microscopy (IFM). PG was localized to cells demonstrating mononuclear and fibroblastic morphology primarily in and around areas of vascularization and inflammation. CD68+ macrophages and to a lesser degree CD90+ synovial sublining fibroblasts. In multiplex assay analysis of synovial fluid cytokine levels, IL-6 and PG abundance were positively correlated. Fibroblasts and macrophages stimulated with PG in vitro secreted high levels of innate cytokines, paricularly IL-6 when measured by supernatant cytokine quantification. Together these data support the hypothesis that PG in synovial tissue drives joint inflammation in OA.

Diagnostic and Predictive Efficacy of Synovial Fluid Versus Serum C-Reactive Protein Levels for Periprosthetic Joint Infection and Reimplantation Success

BackgroundA 2-stage exchange revision for periprosthetic joint infection (PJI) is associated with major risks for reinfection. Although serum markers are frequently used for diagnosis, their effectiveness remains debatable. Synovial fluid markers may offer a more accurate diagnosis of PJI; however, the importance of these biomarkers, notably synovial fluid C-reactive protein (syCRP), remains controversial, particularly in the context of reimplantation. The present study aimed to clarify these diagnostic uncertainties by evaluating the diagnostic efficacy of syCRP versus serum CRP (seCRP) levels in the context of PJI and recurring or persisting infections before reimplantation. MethodsA total of 186 patients were enrolled and divided into 2 groups: aseptic revision (n = 112) and PJI revision (n = 74). Of the PJI group, 65 were categorized as success and 9 as failure, based on the presence of recurrent or persistent infection before reimplantation. The syCRP and seCRP levels and their changes were assessed preoperatively and in the first-stage and second-stage revisions. Additionally, receiver operating characteristic (ROC) curves and area under the ROC curves (AUCs) were analyzed. ResultsBoth seCRP and syCRP levels were significantly elevated in the PJI group compared with the aseptic group (P < .001). The ROC curve analysis highlighted the enhanced diagnostic accuracy of syCRP for PJI, with an AUC of 0.93 versus 0.80 for seCRP. Furthermore, syCRP proved to be more reliable in predicting reimplantation success, exhibiting an AUC of 0.86 versus 0.63 for seCRP. In evaluating trends in CRP levels to determine reimplantation timing, changes in syCRP levels demonstrated superior diagnostic utility, exhibiting an AUC of 0.79 versus 0.63 for changes in seCRP levels. ConclusionsIn assessing PJI and infections before reimplantation, syCRP may offer enhanced accuracy compared with seCRP. Nevertheless, variations in both syCRP and seCRP levels did not consistently predict the outcome of reimplantation.

The Relationship Between Intra-articular Fracture Energy and a Patient's Inflammatory Response.

Prior studies have demonstrated elevated inflammatory cytokine concentrations in the synovial fluid of articular fracture patients postinjury. Similarly, CT-based fracture energy measurements have been correlated with posttraumatic osteoarthritis risk after pilon fracture. The purpose of this study was to determine the associations between synovial fluid cytokine levels, fracture energy, and overall trauma to the body in articular fracture patients. Acute tibial plateau, tibial plafond, and rotational ankle fracture patients were prospectively enrolled from December 2011 through January 1, 2019. Synovial fluid concentrations of interleukin-1 beta, interleukin-1 receptor antagonist, IL-6, IL-8, IL-10, matrix metallopeptidase-1, MMP-3, and MMP-13 were quantified. Patient CT scans were used to calculate fracture energy. The Injury Severity Score (ISS) was used to relate cytokine levels to whole-body injury severity. Spearman rho correlation coefficients were calculated to assess the relationship between injury severity metrics and synovial fluid cytokine, chemokine, and matrix metallopeptidase concentrations. Eighty-seven patients were enrolled with 42 had a tibial plateau fractures (OTA/AO 41B1-2, 41B2-14, 41B3-3, 41C1-3, 41C2-4, 41C3-16), 24 patients had a tibial plafond fracture (OTA/AO 43B1-2, 43B2-4, 43B3-5, 43C1-2, 43C2-3, 43C3-8), and 21 had a rotational ankle fracture (OTA/AO 44B1-3, 44B2-3, 44B3-6, 44C1-4, 44C2-5). Fracture energy significantly differed between fracture patterns, with ankle fractures involving substantially less fracture energy (median = 2.92 J) than plafond (10.85 J, P < 0.001) and plateau fractures (13.05 J, P < 0.001). After adjustment for multiple comparisons, MMP-3 was significantly correlated with transformed fracture energy (r = 0.41, 95% confidence interval [CI], 0.22-0.58, P < 0.001), while IL-1β was significantly correlated with the Injury Severity Score (Spearman ρ = 0.31, 95% CI, 0.08-0.49, P = 0.004). Synovial fluid MMP-3 concentration was significantly correlated with CT-quantified fracture energy in intra-articular fracture patients. Given that in clinical practice fracture energy tends to correlate with posttraumatic osteoarthritis risk, MMP-3 may warrant further investigation for its role in posttraumatic osteoarthritis development after articular fracture. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The effect of plasma cytokines on the expression of adiponectin and its receptors in the synovial membrane of joints and the infrapatellar fat pad in patients with rheumatoid arthritis and osteoarthritis

BackgroundRheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA. ObjectiveThe aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA). MethodsBlood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR. ResultsIn OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1β, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1β. ConclusionsAdiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.

Antiarthritic potential of ethanolic extract of Ixora coccinea leaves on complete Freund's adjuvant-induced arthritis in animal model.

Ixora coccinea leaves possess antioxidant, anti-inflammatory, antinociceptive, antimutagenic, and gastroprotective properties. On this background, its antiarthritic potential was evaluated. The objective is to evaluate the effect of Ethanolic extract of Ixora coccinea leaves (EEICL) on complete Freund's adjuvant-induced arthritis in rats. PG research laboratory, Pharmacology Department, MKCG Medical College, Berhampur, Odisha. Thirty-six Wistar albino rats were randomly distributed into sixgroups (n = 6) as follows: Gr 1 (normal control)-DW p.o, Gr-2 (disease control [DC] - Tween 80 p.o), Gr-3 (piroxicam 0.9 mg/kg p.o), Gr-4 (EEICL-1 g/kg, p.o, Gr 4-EEICL-1.5 g/kg p.o, Gr 5-ED50 (0.82 g/kg) + piroxicam (0.45 mg/kg) p.o. After induction of arthritis, drugs, and vehicles were administered daily from 5th to 25th day. On 0, 5th, 10th, 15th, and 25th day, parameters like body weight, rotarod fall time, paw volume displacement, and arthritis index were measured. On the last day, Erythrocyte sedimentation rate (ESR), tissue malondialdehyde (MDA), and histopathological analysis were done. Analysis of parametric data was done by one-way ANOVA and nonparametric data by Kruskal-Wallis test using graph pad prism 7.0. P < 0.05 was considered statistically significant. EEICL (1.5 mg/kg) showed anti-arthritic effect compared with DC. Rotarod fall-off time 137.5 ± 2.5 sec and body weight (139 ± 12.74 g) were increased significantly. The percentage inhibition of paw volume was increased(52%) whereas arthritic score(0.33), ESR(3.51mm/hr), synovial tissue MDA level (0.62±0.13µmol/gm) and Mankin score(2) were reduced significantly as compared to disease control. EEICL has anti-arthritic potential in rat model.

The Hepatokine RBP4 Links Metabolic Diseases to Articular Inflammation.

This study investigates the role of retinol binding protein 4 (RBP4) in an articular context. RBP4, a vitamin A transporter, is linked to various metabolic diseases. Synovial fluid RBP4 levels were assessed in crystalline arthritis (CA) patients using ELISA. RBP4's impact on articular cell types was analysed in vitro through RT-PCR and flow cytometry. Proteomic analysis was conducted on primary human osteoarthritis chondrocytes (hOACs). Synovial fluid RBP4 concentrations in CA patients correlated positively with glucose levels and negatively with synovial leukocyte count and were elevated in hypertensive patients. In vitro, these RBP4 concentrations activated neutrophils, induced the expression of inflammatory factors in hOACs as well as synoviocytes, and triggered proteomic changes consistent with inflammation. Moreover, they increased catabolism and decreased anabolism, mitochondrial dysfunction, and glycolysis promotion. Both in silico and in vitro experiments suggested that RBP4 acts through TLR4. This study identifies relevant RBP4 concentrations in CA patients' synovial fluids, linking them to hypertensive patients with a metabolic disruption. Evidence is provided that RBP4 acts as a DAMP at these concentrations, inducing robust inflammatory, catabolic, chemotactic, and metabolic responses in chondrocytes, synoviocytes, and neutrophils. These effects may explain RBP4-related metabolic diseases' contribution to joint destruction in various rheumatic conditions like CA.

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis.

Osteoarthritis (OA) is a complex disease of whole joints with progressive cartilage matrix degradation and chondrocyte transformation. The inflammatory features of OA are reflected in increased synovial levels of IL-1β, IL-6 and VEGF, higher levels of TLR-4 binding plasma proteins and increased expression of IL-15, IL-18, IL-10 and Cox2, in cartilage. Chondrocytes in OA undergo hypertrophic and senescent transition; in these states, the expression of Sox-9, Acan and Col2a1 is suppressed, whereas the expression of RunX2, HIF-2α and MMP-13 is significantly increased. NF-kB, which triggers many pro-inflammatory cytokines, works with BMP, Wnt and HIF-2α to link hypertrophy and inflammation. Altered carbohydrate metabolism and the upregulation of GLUT-1 contribute to the formation of end-glycation products that trigger inflammation via the RAGE pathway. In addition, a glycolytic shift, increased rates of oxidative phosphorylation and mitochondrial dysfunction generate reactive oxygen species with deleterious effects. An important surveyor mechanism, the YAP/TAZ signaling system, controls chondrocyte differentiation, inhibits ageing by protecting the nuclear envelope and suppressing NF-kB, MMP-13 and aggrecanases. The inflammatory microenvironment and synthesis of key matrix components are also controlled by SIRT1 and mTORc. Senescent chondrocytes represent the functional end stage of hypertrophic differentiation and characteristically upregulate p16 and p21, but also a variety of inflammatory cytokines, chemokines and metalloproteinases, developing the senescence-associated secretory phenotype. Senolysis with dendrobin, miR29b-5p and other agents has been shown to be efficient under experimental conditions, and appears to be a promising tool for the treatment of OA, as it restores COL2A1 and aggrecan synthesis, suppressing NF-kB and destructive metalloproteinases.