Synovial Levels Research Articles

Incorporation of Baccharis dracunculifolia DC (Asteraceae) leaf extract into phosphatidylcholine-cholesterol liposomes improves its anti-inflammatory effect in vivo

The aerial parts of Baccharis dracunculifolia (BdE) is used in the Brazilian folk medicine to treat inflammatory conditions. Here we examined the ability of free and liposomal BdE to modulate reactive oxygen species generation in human neutrophils in vitro and zymosan-induced acute joint inflammation in Wistar rats. We prepared biocompatible liposomes of soya phosphatidylcholine and cholesterol with low diameter, homogeneous size distribution, and neutral surface charge. Free BdE decreased joint swelling, total leucocyte and neutrophil infiltration, and the synovial levels of tumour necrosis factor-α and interleukins 6 and 1β. Incorporation of BdE into liposomes preserved its capacity to inhibit the neutrophil superoxide anion and total reactive oxygen species generation, and improved its anti-inflammatory effect in vivo by decreasing the effective BdE dose by nearly sixfold. The same liposome type lowered the effective dose of caffeic acid by nearly sixteenfold. Therefore, incorporation of BdE into phosphatidylcholine-cholesterol liposomes improves its anti-inflammatory effect.

The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis

BackgroundMIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA).MethodsStarting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.ResultsIn ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55–57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25–37% lower macroscopic scores in the femur condyles and 13–33% lower macroscopic scores in the tibial plateaus.ConclusionsMIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

Elevated Levels of Soluble ST2 were Associated with Rheumatoid Arthritis Disease Activity and Ameliorated Inflammation in Synovial Fibroblasts.

Background:Much evidence has demonstrated that interleukin (IL)-33 plays an important role in rheumatoid arthritis (RA). However, there have been limited studies about soluble ST2, a receptor for IL-33, in RA. The aims of this study were to detect the levels of ST2 in the serum and synovial fluid of RA patients and to reveal the association of these levels with disease activity and the function of ST2 in RA.Methods:A total of 56 RA patients and 38 age-matched healthy controls were enrolled in this study. Synovial fluid samples were collected from another 30 RA patients and 20 osteoarthritis patients. Serum and synovial fluid levels of ST2 were measured by ELISA. In addition, the levels of ST2 in the serum of RA patients before and after therapy were detected. The function of ST2 in RA was revealed by the results of an in vitro cell assay, where recombinant ST2 proteins were used to treat peripheral blood mononuclear cells (PBMCs) and RA synovial fibroblasts (RASFs).Results:Serum-soluble ST2 levels were significantly higher in RA patients (127.14 ± 61.43 pg/ml) than those in healthy controls (78.37 ± 41.93 pg/ml, P < 0.01). Synovial fluid-soluble ST2 levels (41.90 ± 33.58 pg/ml) were much higher in RA patients than those in osteoarthritis patients (19.71 ± 16.72 pg/ml, P < 0.05). RA patients who received effective therapy for 6 months showed decreased serum-soluble ST2 levels (113.01 ± 53.90 pg/ml) compared to baseline (139.59 ± 68.36 pg/ml) (P = 0.01). RA patients with high disease activity had higher serum-soluble ST2 levels (162.02 ± 56.78 pg/ml) than those with low disease activity (94.67 ± 40.27 pg/ml, P = 0.001). Soluble ST2 did not affect IL-1β, IL-6, IL-8, or tumor necrosis factor-α (TNF-α) expression in PBMCs from RA patients. However, soluble ST2 ameliorated the expressions of IL-33 and IL-1β but not that of IL-6, IL-8, or TNF-α in resting RASFs. Interestingly, in the RASFs stimulated by TNF-α plus IL-1β, soluble ST2 showed extensive suppressive effects on the expression of IL-6, IL-8, and TNF-α.Conclusion:Elevated levels of ST2 in the serum and synovial fluid were associated with disease activity and ameliorated IL-33 expression and IL-33-induced inflammation in RASFs, suggesting that soluble ST2 might be a potential therapeutic candidate for RA.

Correlation between protein YKL-40 and ultrasonographic findings in active knee osteoarthritis.

A prospective study with fifty consecutive patients with active knee OA (diagnosed based on the American College of Rheumatology criteria for OA with radiographic confirmation) was performed. Concentrations of YKL-40 in serum and synovial fluid were measured by ELISA. US examinations - Gray scale (GS) US and Power Doppler (PD) US - of the knee was performed according to international guidelines. The suprapatellar, medial and lateral parapatellar recesses were scanned in each knee to evaluate synovial hypertrophy and vascularization. Forty women (mean age 61.50±11.33 years old) and 10 men (aged 68.50±6.60 years old) were enrolled. We found that the synovial level of the glycoprotein (237.80±104.08 ng/ml) was significantly higher compared to the serum concentration (112.83±60.61 ng/ml, p<0.001). The serum concentration in OA patients was higher comparing with age-matched healthy controls (84.19±11.39 ng/ml) (p<0.05). A statistically significant association between YKL- 40 in synovial fluid and serum levels was shown. We determined a moderately positive linear relationship between the synovial level of the glycoprotein and the serum concentration. No association between the levels of inflammatory markers - erythrocyte sedimentation rate and C-reactive protein - and YKL-40 concentrations was detected. Our study revealed a strong relationship between YKL-40 in synovial fluid and GS US and feeble with PD US. YKL-40 correlated with inflammatory activity in knee joints and neovascularization detected by US. YKL-40 is involved in the pathogenesis of OA synovitis. Evaluation of YKL-40 levels in parallel with US might provide more sensitive and reliable information for the diagnosis and understanding of OA.

Analysis of synovial fluid visfatin level in temporomandibular joint disorders

Background: Biochemical analysis of synovial fluid (SF) is an important means of understanding the pathogenesis of temporomandibular disorder (TMD) and confirming diagnoses made using traditional methods.Objective: The aim of this study was to determine whether or not SF visfatin levels can serve as a biochemical marker in the diagnosis of TMD.Method: Sixty samples of SF were obtained from 60 patients with internal derangement (ID) or osteoarthritis (OA). Visfatin in the SF was examined by enzyme-linked immunosorbent assay (ELISA).Result: Visfatin levels showed positive correlations with TMD pain and ID stage and a negative correlation with maximum mouth opening. In addition, Visfatin levels in joints with OA changes in the condyle were significantly higher in comparison to joints with no OA changes.Conclusion: Within the limitations of this study, it can be concluded that visfatin may play a role in the pathogenesis of TMD.

Circulating levels of proinflammatory mediators as potential biomarkers of post-traumatic knee osteoarthritis development

BackgroundThe identification of biomarkers of post-traumatic osteoarthritis (PTOA) progression is of clinical importance. The aims of this study were: (1) to assess the abilities of various soluble proinflammatory mediators in plasma to distinguish patients with knee PTOA from controls; (2) to determine the correlations between the mediators in plasma and those mediators in synovial fluid (SF); and (3) to explore the associations of the mediators with radiographic PTOA severity.Materials and methodsThe concentrations of IL-1β, IL-6, IL-18, TNFα, and leptin were measured using ELISA. Nitric oxide was determined as nitrite/nitrate (NOx) using the Griess reaction.ResultsWe included 171 subjects (134 PTOA patients and 37 controls) and excluded patients with rheumatoid arthritis or gout. The ROC curve of plasma NOx had the highest AUC, a specificity of 100%, and a sensitivity of 84.4%. The combination of IL-6 and leptin proved to be the most discriminatory, with an AUC value of 0.933, a specificity of 96.7%, and a sensitivity of 85.7%. The levels of NOx, IL-6, IL-18, and leptin in plasma were significantly correlated with their levels in SF. Leptin levels in both plasma (p = 0.036) and SF (p = 0.041) and the synovial IL-18 level (p = 0.045) were correlated with the Kellgren–Lawrence (KL) grade. Early-stage PTOA (KL 1–2) was associated with a high concentration of IL-1β in plasma before and after (OR 6.235, 95% CI 1.362 to 28.552, p = 0.018) adjusting for age, gender, and BMI.ConclusionsCirculating NOx level and a combination of IL-6 and leptin permitted the strongest discrimination of patients with PTOA from controls. PTOA severity was correlated with leptin levels in plasma and SF and with the synovial IL-18 level. Early PTOA was associated with the circulating level of IL-1β.Level of evidenceIII (case–control study).

Comparison of Adenosine Deaminase Level in Serum and Synovial Fluid in Patients with Juvenile Idiopathic Arthritis and Its Relation to Inflammatory Acute Phase Reactants

Background: In JIA, cell-mediated immune response results in secretion of different inflammatory products from activated lymphocytes, macrophages, fibroblasts and leukocytes in synovial joints. Adenosine deaminase (ADA) regulates this immune system activity by metabolizing adenosine through purine metabolic pathway. Objectives: The aim of this study was to compare the level of serum ADA with synovial fluid ADA in JIA patients and to see whether it can be utilized as a marker for the activity of the disease Methods: JIA was diagnosed based on International League of Associations for Rheumatology diagnosis criteria. ADA was measured using special kits. Results: 80% of the patients had oligoarticular and 20% polarticulare JIA. There was a significant relation between erythrocyte sedimentation rate (ESR) and high level of synovial fluid ADA. Synovial ADA level was significantly higher than serum ADA in polyarticular JIA. C-reactive protein (CRP), leukocytes and platelets count were increased in high levels of synovial fluid ADA. No correlation was observed between level of serum and synovial fluid ADA. Conclusions: Synovial fluid ADA seems a more precise index than serum ADA to assess the inflammatory condition. In addition, acute-phase response reactants such as ESR, CRP, and platelets count could be suitable predicting parameters for arthritis.

Cartilage Oligomeric Matrix Protein Levels in Synovial Fluid in Patients With Primary Knee Osteoarthritis And Healthy Controls: A Preliminary Comparative Analysis With Serum Cartilage Oligomeric Matrix Protein.

This study aims (i) to compare synovial fluid and serum cartilage oligomeric matrix protein levels in patients with primary knee osteoarthritis and healthy controls, (ii) compare variations of synovial fluid and serum cartilage oligomeric matrix protein levels according to sex, Kellgren-Lawrence grades, and daytime sampling, and (iii) correlate the synovial fluid and serum cartilage oligomeric matrix protein levels with age, severity of disease, and daytime sampling. One hundred and twenty-four individuals (44 males, 80 females; median age 66 years; range 42 to 87 years) were diagnosed with primary knee osteoarthritis according to the American College of Rheumatology guidelines. Additionally, 105 healthy healthy individuals (49 males, 56 females; median age 50 years; range 30 to 75 years) were included as the control group. For both groups, a thorough clinical history and physical examination were performed. Moreover, weight-bearing anteroposterior and lateral bending 30 degrees knee X-rays were collected. Cartilage oligomeric matrix protein in serum and synovial fluid was measured by enzyme-linked immunosorbent assay. Total synovial fluid cartilage oligomeric matrix protein levels were considerably higher than total serum levels for both groups. Levels of cartilage oligomeric matrix protein in synovial fluid and serum were higher in patients than in controls for both sexes. However, only cartilage oligomeric matrix protein levels in synovial fluid were higher in female patients. The levels of synovial fluid cartilage oligomeric matrix protein were significantly higher when sampling after 12 pm. A positive correlation was found between synovial fluid and serum cartilage oligomeric matrix protein levels, age, and daytime sampling. These findings may suggest a possible role for synovial fluid and serum cartilage oligomeric matrix protein as a measure for primary knee osteoarthritis. However, more studies need to be performed to address other factors that may influence the levels of cartilage oligomeric matrix protein in synovial fluid and serum.

Diagnostic Value of Synovial White Blood Cell Count and Serum C-Reactive Protein for Acute Periprosthetic Joint Infection After Knee Arthroplasty

BackgroundThe diagnosis of periprosthetic joint infection (PJI) remains difficult, particularly in acute postoperative stage. The purpose of this study was to investigate the optimal cutoff value of synovial white blood cell (WBC) count, percentage of polymorphonuclear cells, erythrocyte sedimentation rate, and C-reactive protein (CRP) for diagnosing early postoperative infection after knee joint arthroplasty. MethodsWe retrospectively reviewed primary total knee arthroplasties and unicompartmental knee arthroplasties, with a knee aspiration within 3 weeks of surgery, from January 2006 to November 2016. Twelve infected cases and 185 uninfected cases met the inclusion criteria of our study. We compared the laboratory parameters (synovial WBC count, percentage of polymorphonuclear cells, erythrocyte sedimentation rate, and CRP levels) between the 2 groups. Receiver operating characteristic curves were constructed to determine the optimal cutoff values for each parameter. Each parameter was studied to determine its sensitivity, specificity, and positive and negative predictive values (PPV and NPV) in diagnosing acute PJI. ResultsThere were 2 optimal cutoff values for synovial WBC count and CRP levels. With the cutoff value of synovial WBC set at 11,200 cells/μL, acute PJI could be diagnosed with the highest sensitivity (100%) and specificity (98.9%); with the cutoff value set at 16,000 cells/μL, the best PPV and NPV were found (100% and 99.5%, respectively). Similarly, the CRP level >34.9 mg/L had the best sensitivity (100%) and specificity (90.3%), whereas the CRP level >74.5 mg/L had the best PPV (100%) and NPV (99.2%). ConclusionSynovial WBC count and CRP levels are useful in diagnosing acute PJI between 1 and 3 weeks after primary knee arthroplasty.

Erratum to: Association between serum and synovial fluid Dickkopf-1 levels with radiographic severity in primary knee osteoarthritis patients.

Erratum to: Association between serum and synovial fluid Dickkopf-1 levels with radiographic severity in primary knee osteoarthritis patients.

Increase and regulation of synovial calcitonin gene-related peptide expression in patients with painful knee osteoarthritis.

BackgroundRecent studies suggest that the vasodilatory neuropeptide calcitonin gene-related peptide (CGRP) is localized in the synovial tissue and may be involved in the pathology of hip and knee osteoarthritis (OA). However, the regulation and relationship between pain and CGRP expression levels in the synovial tissue of human OA patients are not fully understood.MethodsSynovial tissues were harvested from 74 participants with radiographic knee OA (unilateral Kellgren/Lawrence grades 3–4) during total knee arthroplasty. CGRP-expressing cells in the resected tissue were identified by immunohistochemical analyses. To examine CGRP expression levels, CD14-positive (CD14+) (macrophage-rich cell fraction) and CD14-negative (CD14−; fibroblast-rich cell fraction) cells were isolated from the synovial tissue. To investigate the involvement of prostaglandin E2 (PGE2) in the regulation of CGRP expression, cultured CD14− and CD14+ cells were stimulated with PGE2. In addition, CGRP expression levels in the synovial tissue of OA patients with strong/severe (visual analog scale [VAS]≥6) and mild/moderate pain (VAS<6) were compared.ResultsCGRP-positive cells were detected in the intimal lining layer and comprised both CD14− and CD14+ cells. CGRP expression in non-cultured CD14− fractions was significantly higher than that in CD14+ fractions. The expression levels of CGRP were significantly increased in cultured CD14− cell fractions treated with exogenous PGE2, compared to untreated CD14− cell fractions. In contrast, treatment with PGE2 did not increase CGRP regardless of whether or not CD14+ cells expressed CGRP. Furthermore, CGRP expression in the VAS≥6 group was also significantly higher than that in the VAS<6 group.ConclusionThese findings suggest that CGRP expression in the synovial fibroblasts is regulated by the COX-2/PGE2 pathway and that elevation of synovial CGRP levels may contribute to OA pain.

Synovial calprotectin

Recently, several synovial biomarkers have been introduced into the algorithm for the diagnosis of a prosthetic joint infection (PJI). Alpha defensin is a promising biomarker, with a high sensitivity and specificity, but it is expensive. Calprotectin is a protein that is present in the cytoplasm of neutrophils, is released upon neutrophil activation and exhibits anti-microbial activity. Our aim, in this study, was to determine the diagnostic potential of synovial calprotectin in the diagnosis of a PJI. In this pilot study, we prospectively collected synovial fluid from the hip, knee, shoulder and elbow of 19 patients with a proven PJI and from a control group of 42 patients who underwent revision surgery without a PJI. PJI was diagnosed according to the current diagnostic criteria of the Musculoskeletal Infection Society. Synovial fluid was centrifuged and the supernatant was used to measure the level of calprotectin after applying a lateral flow immunoassay. The median synovial calprotectin level was 991 mg/L (interquartile range (IQR) 154 to 1787) in those with a PJI and 11 mg/L (IQR 3 to 29) in the control group (p < 0.0001). Using a cut-off value of 50 mg/L, this level showed an excellent diagnostic accuracy, with an area under the curve of 0.94. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) was 89%, 90%, 81% and 95% respectively. The NPV was 97% in the nine patients with a chronic PJI. Synovial calprotectin may be a valuable biomarker in the diagnosis of a PJI, especially in the exclusion of an infection. With a lateral flow immunoassay, a relatively rapid quantitative diagnosis can be made. The measurement is cheap and is easy to use. Cite this article: Bone Joint J 2017;99-B:660-5.

Association between serum and synovial fluid Dickkopf-1 levels with radiographic severity in primary knee osteoarthritis patients.

Primary knee osteoarthritis (OA) contributes to disability among middle-aged and elderly people. Dickkopf-1 (Dkk-1) and sclerostin are inhibitors of Wnt/β-catenin signaling pathway implicated in regulation of cartilage homeostasis and bone formation, respectively. We aim to investigate the association between the serum(s) and synovial fluid (SF) Dkk-1 and sclerostin levels and disease severity in patients with primary knee OA. Forty patients aged 56-87years with primary knee OA and 20 healthy individuals were recruited. Weight-bearing anteroposterior radiographs of the affected knee were used to determine the disease severity according to Kellgren and Lawrence criteria. Dkk-1 and sclerostin levels in serum and SF were measured by ELISA. SF Dkk-1 levels were significantly higher in the OA, compared to control group (180±182 vs 128±330pg/ml, p<0.001). However, OA patients did not differ significantly regarding the sDkk-1 concentrations compared to healthy controls (1289.8pg/ml vs 1214.1, respectively, p=0.630). SF Dkk-1 levels in Kellgren and Lawrence (KL) grade 4 were significantly elevated compared to those of KL grades 2 and 3 (1.97 vs 2.23pg/ml, p=0.017, log transformed because data were not normally distributed), whereas sDkk-1 levels between those groups demonstrated marginally statistically significant difference (1111.8 vs 1415.9pg/ml, p=0.057). SFSclerostin and sSclerostin levels did not have any significant difference between the OA and control groups. SF Dkk-1 levels are positively related to the severity of joint damage in knee OA. Sclerostin levels failed to substantiate an association to knee OA progression. Dkk-1 could play a potential role in the degenerative process of OA. Thus, DKK-1 may emerge as a promising future therapeutic manipulation of OA.

Calgizzarin (S100A11): a novel inflammatory mediator associated with disease activity of rheumatoid arthritis

BackgroundCalgizzarin (S100A11) is a member of the S100 protein family that acts in different tumors by regulating a number of biologic functions. Recent data suggest its association with low-grade inflammation in osteoarthritis (OA). The aim of our study is to compare S100A11 expression in the synovial tissues, synovial fluid and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to characterize the potential association between S100A11 and disease activity.MethodsS100A11 protein expression was detected in synovial tissue from patients with RA (n = 6) and patients with OA (n = 6) by immunohistochemistry and immunofluorescence. Serum and synovial fluid S100A11 levels were measured by ELISA in patients with RA (n = 40) and patients with OA (n = 34). Disease activity scores in 28 joints based on C-reactive protein (DAS28-CRP) were used to assess disease activity. Cytokine content in peripheral blood mononuclear cells (PBMCs), synovial fibroblasts (SFs) and synovial fluid was analysed by ELISA, western blotting or cytometric bead array.ResultsS100A11 expression was significantly up-regulated in the synovial lining and sublining layers (p < 0.01) and vessels (p < 0.05) of patients with RA compared to patients with OA, and was associated with fibroblasts and T cells. S100A11 was significantly increased in synovial fluid (p < 0.0001) but not in serum (p = 0.158) from patients with RA compared to patients with OA when adjusted for age and sex. Synovial fluid S100A11 correlated with DAS28 (r = 0.350, p = 0.027), serum CRP (r = 0.463, p = 0.003), synovial fluid leukocyte count (r = 0.677, p < 0.001), anti-cyclic citrullinated peptide antibodies (anti-CCP) (r = 0.424, p = 0.006) and IL-6 (r = 0.578, p = 0.002) and IL-8 (r = 0.740, p < 0.001) in synovial fluid from patients with RA. PBMCs and SFs isolated from patients with RA synthesized and spontaneously secreted higher levels of S100A11 in comparison with PBMCs and SFs from patients with OA (p = 0.011 and 0.03, respectively). S100A11 stimulated the production of the pro-inflammatory cytokine IL-6 by PBMCs (p < 0.05) and SFs (p < 0.01).ConclusionsOur data provide the first evidence of S100A11 up-regulation and its association with inflammation and disease activity in patients with RA.

Calprotectin levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis

ABSTRACTObjective: We evaluated the relationship between calprotectin levels and rheumatoid arthritis (RA), and the correlation between plasma/serum calprotectin and RA activity.Methods: We searched PUBMED, EMBASE, and Cochrane databases and performed meta-analyses comparing plasma/serum or synovial fluid calprotectin levels in RA patients and controls, and correlation coefficients between calprotectin levels and disease activity for 28 joints (DAS28) as well as C-reactive protein (CRP) in RA patients.Results: Sixteen studies including 849 RA patients and 266 controls were available for meta-analysis. Meta-analysis showed that calprotectin levels were significantly higher in the RA group than in the control group (SMD = 2.337, 95% CI = 1.544–3.130, p < 1.0 × 10–8). Stratification by rheumatoid factor (RF) status revealed significantly elevated calprotectin levels in the RF-positive RA group compared to that of the RF-negative RA group (SMD = 0.574, 95% CI = 0.345–0.804, p = 9.2 × 10–7). Meta-analysis of correlation coefficients identified a significant positive correlation between calprotectin levels and CRP or DAS28 (correlation coefficient for CRP = 0.566, 95% CI = 0.512–0.615, p < 1.0 × 10–8; correlation coefficient for DAS28 = 0.438, 95% CI = 0.269–0.518, p = 2.5 × 10–6). Calprotectin levels in synovial fluid were significantly higher in the RA group than in the control group (SMD = 2.891, 95% CI = 1.067–4.715, p = 0.002).Conclusions: Our meta-analysis demonstrates that circulating and synovial fluid calprotectin levels are high in patients with RA, and that circulating calprotectin levels positively correlate with RA activity.

The cytokine expression in synovial membrane and the relationship with pain and pathological findings at hip arthroscopy

BackgroundSynovial membrane inflammation is the most common finding presenting during hip arthroscopy, and may play a role in hip pain. We sought to determine the relationships between synovial cytokine levels, hip pain, and arthroscopic findings of the hip joint.MethodsWe prospectively included 33 patients who underwent arthroscopic hip surgery (34 hips). For all patients, radiographs and severity of pain were evaluated preoperatively. During arthroscopy, we classified the chondral injury and synovitis, noted the incidence of labral tear and its instability, and a sample of the synovial membrane was harvested for quantitative PCR to determine levels of TNFα, IL1β, IL6, ADAMTS4, MMP1, and MMP3. The relationships between the levels of these cytokines, severity of hip pain, and the pathological findings during arthroscopy were examined.ResultsPain intensity and cytokine levels were not significantly different between patients with labral tear or instability and those without. By contrast, the expression of TNFα, IL1β, IL6, and MMP1 mRNA was significantly higher in patients with diffuse synovitis than in patients with focal synovitis. VAS score during rest showed significant positive correlation with IL6 (r = 0.45, p < 0.01), while VAS score on walking showed a positive correlation with TNFα (r = 0.47, p < 0.01), and ADAMTS4 (r = 0.51, p < 0.01). The modified Harris Hip pain score showed a negative correlation with TNFα (r = −0.38, p = 0.04) and IL6 (r = −0.58, p < 0.01).ConclusionsThe severity of synovitis and chondral injury are considered to be more important in the pathology of hip pain than labral tear or instability. Inflammatory cytokines, especially TNFα and IL6 might play an important role in the pathogenesis of pain in patients indicated for hip arthroscopy, possibly depending on the severity of synovitis.

Decreased synovial fluid ghrelin levels are linked with disease severity in primary knee osteoarthritis patients and are increased following laser therapy

BackgroundGhrelin has been proved to inhibit inflammation and promote cartilage growth. So far, its role in patients with primary knee osteoarthritis has not been investigated. ObjectiveThe current study was performed to explore the serum and synovial ghrelin levels as well as the relationship between ghrelin levels and disease severity in primary knee OA patients. Methods52 primary knee OA patients were recruited in the study. 52 sex and age-matched patients visiting our hospital for regular body check were selected as controls. The serum and synovial fluid ghrelin levels were examined by enzyme linked immunosorbent assay (ELISA) before treatment, one week and four weeks after laser therapy, respectively. The inflammation markers IL-6 and TNF-α were also investigated. The radiographic progression was assessed by Kellgren-Lawrence (K-L) grade scale and the symptomatic severity was evaluated by visual analog scale (VAS), Lequesne index and Lysholm scores. The Receiver Operating Characteristic (ROC) analysis curve was conducted to test the diagnostic value of ghrelin, IL-6 and TNF-α for radiographic progression. ResultsNo significant difference of serum ghrelin levels was found between knee OA patients and healthy controls. Synovial fluid ghrelin concentrations were significantly negatively correlated with K-L grading (r=−0.591, P<0.001).Attenuated synovial fluid ghrelin levels were also related to clinical severity determined by Lequesne index (r=−0.308, P=0.025),VAS scores (r=−0.591, P<0.001) and Lysholm scores (r=0.381, P=0.005).In addition, ghrelin levels were also negatively associated with TNF-α (r=−0.424, P=0.002) and IL-6 concentrations (r=−0.428, P=0.002). ROC curve analysis demonstrated that ghrelin exhibited more diagnostic value than IL-6 and TNF-α for assessing radiographic progression in medium-late stage. ConclusionsDecreased synovial fluid ghrelin levels are related to disease severity in patients with primary osteoarthritis and are increased following laser therapy. Local application of ghrelin may serve as an adjunctive therapy for knee OA.

High synovial fluid interleukin-6 levels are associated with increased matrix metalloproteinase levels and severe radiographic changes in osteoarthritis patients

High synovial fluid interleukin-6 levels are associated with increased matrix metalloproteinase levels and severe radiographic changes in osteoarthritis patients

Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair

High-fat diet-induced obesity is a major risk factor for osteoarthritis (OA) and diminished wound healing. The objective of this study was to determine the associations among serum and synovial fluid lipid levels with OA, synovitis, adipokine levels, and wound healing in a pre-clinical obese mouse model of OA. Male C57BL/6 J mice were fed either a low-fat (10% kcal) or one of three high-fat (HF, 60% kcal) diets rich in saturated fatty acids (SFAs), ω-6 or ω-3 polyunsaturated FAs (PUFAs). OA was induced by destabilization of the medial meniscus. Mice also received an ear punch for evaluating wound healing. Serum and synovial fluid were collected for lipidomic and adipokine analyses. We demonstrated that the serum levels of ω-3 PUFAs were negatively correlated with OA and wound size, but positively correlated with adiponectin levels. In contrast, most ω-6 PUFAs exhibited positive correlations with OA, impaired healing, and inflammatory adipokines. Interestingly, levels of pentadecylic acid (C15:0, an odd-chain SFA) and palmitoleic acid were inversely correlated with joint degradation. This study extends our understanding of the links of FAs with OA, synovitis and wound healing, and reports newly identified serum and synovial fluid FAs as predictive biomarkers of OA in obesity.