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Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

ABSTRACT: Osteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed their immunostimulatory properties.We used mass spectrometry to survey the proteins present in the synovial fluid of patients with knee OA. We used a multiplex bead-based immunoassay to measure levels of inflammatory cytokines in serum and synovial fluid from patients with knee OA and from patients with rheumatoid arthritis (RA), as well as in sera from healthy individuals. Significant differences in cytokine levels between groups were determined by significance analysis of microarrays, and relations were determined by unsupervised hierarchic clustering. To assess the immunostimulatory properties of a subset of the identified proteins, we tested the proteins' ability to induce the production of inflammatory cytokines by macrophages. For proteins found to be stimulatory, the macrophage stimulation assays were repeated by using Toll-like receptor 4 (TLR4)-deficient macrophages.We identified 108 proteins in OA synovial fluid, including plasma proteins, serine protease inhibitors, proteins indicative of cartilage turnover, and proteins involved in inflammation and immunity. Multiplex cytokine analysis revealed that levels of several inflammatory cytokines were significantly higher in OA sera than in normal sera, and levels of inflammatory cytokines in synovial fluid and serum were, as expected, higher in RA samples than in OA samples. As much as 36% of the proteins identified in OA synovial fluid were plasma proteins. Testing a subset of these plasma proteins in macrophage stimulation assays, we found that Gc-globulin, ?1-microglobulin, and ?2-macroglobulin can signal via TLR4 to induce macrophage production of inflammatory cytokines implicated in OA.Our findings suggest that plasma proteins present in OA synovial fluid, whether through exudation from plasma or production by synovial tissues, could contribute to low-grade inflammation in OA by functioning as so-called damage-associated molecular patterns in the synovial joint.

SUBMITTER: Sohn DH

PROVIDER: S-EPMC3392793 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

Sohn Dong Hyun DH Sokolove Jeremy J Sharpe Orr O Erhart Jennifer C JC Chandra Piyanka E PE Lahey Lauren J LJ Lindstrom Tamsin M TM Hwang Inyong I Boyer Katherine A KA Andriacchi Thomas P TP Robinson William H WH

Arthritis research & therapy 20120108 1

<h4>Introduction</h4>Osteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed ...[more]

PMID: 22225630

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Project description:BACKGROUND:Osteoarthritis is a mechanical abnormality characterized by chronic joint pain associated with degeneration of the articular cartilage, synovitis, and local inflammation, leading to loss of function and pain. A connection exists between the peripheral nervous system and inflammatory joint degeneration. The process by which inflammation is influenced by the nervous system is known as neuroinflammation. One of the neuropeptides involved in peripheral neuroinflammation is nociceptin, a peptide related to the opioid class of substances. Nociceptin has both pro- and anti-inflammatory effects. Some studies show that nociceptin can be measured in synovial fluid, while other studies have not been able to detect it. The presence of nociceptin in synovial fluid could imply a molecular role for the neuropeptide in the joint, both physiologically as well as pathophysiologically. The goal of this pilot study was to determine whether nociceptin was present in the synovial fluid of osteoarthritic knees. METHODS:Patients undergoing primary total knee arthroplasty were enrolled after Institutional Review Board approval was obtained. Synovial fluid was aspirated from patients' operative knee joints and blood samples were obtained. A commercially available enzyme Immunoassay kit was used to test for nociceptin. A linear mixed-effects model was developed to account for the repeated measurements and baseline covariates. Least squares (adjusted) means were derived from the model to compare the sample types and to compare subgroups. RESULTS:Twenty patients were included in this study. Nociceptin was detected in the synovial fluid and plasma of all patients. The mean concentration (± standard deviation) of nociceptin in synovial fluid was 28.7 ± 18.2?pg/ml. The mean concentration of nociceptin in plasma was 45.2 ± 24.3?pg/ml pre-procedure, and 40.1 ± 20.6?pg/ml post-tourniquet deflation. The nociceptin concentration in synovial fluid was significantly lower than the nociceptin concentration in plasma, both pre-procedure and post-tourniquet deflation (p = 0.002 and p = 0.016 respectively). The nociceptin concentration in both plasma and synovial fluid was significantly lower in females versus males (p = 0.012). CONCLUSION:We demonstrated that nociceptin is present in synovial fluid and plasma of patients undergoing total knee arthroplasty. This implies a potential role for nociceptin in modulating inflammation in osteoarthritis. TRIAL REGISTRATION:ClinicalTrials.gov , NCT02528916 . Retrospectively registered on August 19, 2015.

Project description:BackgroundChronic, low-grade inflammation of the synovium (synovitis) is a hallmark of osteoarthritis (OA), thus understanding of OA immunobiology, mediated by immune effectors, is of importance. Specifically, monocytes/macrophages (MΦs) are known to be abundantly present in OA joints and involved in OA progression. However, different subsets of OA MΦs have not been investigated in detail, especially in terms of their relationship with patient-reported outcome measures (PROMs). We hypothesized that levels of synovial fluid (SF) MΦ subsets are indicative of joint function and quality of life in patients with OA, and can therefore serve as biomarkers and therapeutic targets for OA.MethodsIn this cohort study, synovial fluid leukocytes (SFLs, N = 86) and peripheral blood mononuclear cells (n = 53) from patients with knee OA were characterized. Soluble MΦ receptors and chemokine (sCD14, sCD163, CCL2, CX3CL1) levels were detected in SF using immunoassays. Linear models, adjusted for sex, age and body mass index, were used to determine associations between SF MΦs and soluble factors with PROMs (N = 83). Pearson correlation was calculated to determine correlation between MΦ subsets, T cells and soluble factors.ResultsSF MΦs were the most abundant SFLs. Within these, the double-positive CD14+CD16+-MΦ subset is enriched in knee OA SF compared to the circulation. Importantly, MΦ subset ratios correlated with PROMs, specially stiffness, function and quality of life. Interestingly, the SF CD14+CD16+-MΦ subset ratio correlated with SF chemokine (C-C motif) ligand 2 (CCL2) levels but not with levels of sCD163 or sCD14; we found no association between PROMs and either SF CCL2, sCD163, sCD14 or CX3CL1 (which was below detection levels). All SF MΦs displayed high levels of HLA-DR, suggesting an activated phenotype. Correlation between OA SF MΦ subsets and activated CD4+ T cell subsets suggests modulation of CD4+ T cell activation by MΦs.ConclusionSF MΦ subsets are associated with knee OA PROMs and display an activated phenotype, which may lead to modulation of CD4+ T cell activation. Knee OA SF MΦ subsets could serve as knee OA function biomarkers and as targets of novel therapeutics.

Project description:Osteoarthritis (OA) is one of the most common causes of disability in aged people, and it is defined as a degenerative arthropathy, characterized by the disruption in joint tissue. The synovium plays a vital role in maintaining the health of the joint by supplying the nutrients to the surrounding tissues and the lubrication for joint movement. While it is well known that all the joint tissues are communicating and working together to provide a functioning joint, most studies on OA have been focused on bone and cartilage but much less about synovium have been reported. The purpose of this review was to investigate the current literature focused on RNA sequencing (RNAseq) of osteoarthritic synovial tissues to further understand the dynamic transcriptome changes occurring in this pivotal joint tissue. A total of 3 electronic databases (PubMed, CINHAL Complete, and Academic Complete) were systematically searched following PRISMA guidelines. The following criteria was used for inclusion: English language, free full text, between the period 2011-2022, size of sample (n > 10), study design being either retrospective or prospective, and RNAseq data of synovial tissue from OA subjects. From the initial search, 174 articles, 5 met all of our criteria and were selected for this review. The RNAseq analysis revealed several differentially expressed genes (DEGs) in synovial tissue. These genes are related to the inflammatory pathway and regulation of the extracellular matrix. The MMP family, particularly MMP13 was identified by three of the studies, indicating its important role in OA. IL6, a key contributor in the inflammation pathway, was also identified in 3 studies. There was a total of 8 DEGs, MMP13, MMP1, MMP2, APOD, IL6, TNFAIP6, FCER1G, and IGF1 that overlapped in 4 out of the 5 studies. One study focused on microbial RNA in the synovial tissue found that the microbes were differentially expressed in OA subjects too. These differentially expressed microbes have also been linked to the inflammatory pathway. Further investigation with more clinical gene profiling in synovial tissue of OA subjects is required to reveal the causation and progression, as well as aid in the development of new treatments.

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Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

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Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4.

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