Osteoarthritis Synovium Research Articles

Danggui niantong decoction attenuates synovial fibrosis through regulating PI3k/AKT signaling pathway.

Danggui Niantong Decoction (DGNTD) is a traditional Chinese medicine compound formula that has been demonstrated to possess efficacy in the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), as well as for dispelling moisture and relieving pain. As mentioned before, DGNTD is essential for synovial inflammation in RA. The primary features of the OA synovial membrane are low-grade inflammation, hyperplasia with enhanced fibroblast-like synoviocytes (FLS) proliferation, and fibrosis, which can cause pain and stiffness. However, it is still unknown how DGNTD functions in the OA synovium. Clarify the influence of DGNTD on OA synovium and investigate potential mechanisms of action. The principal constituents of DGNTD were detected using liquid chromatography-mass spectrometry (LC-MS) analysis. To evaluate the effect of DGNTD on synovial inflammation and fibrosis, a transforming growth factor beta (TGF-β)-stimulated rat FLS cell model and a rat OA animal model based on anterior cruciate ligament transection (ACLT) and partial medial meniscectomy (MMx) were employed. Our results showed that 322 components were detected using LC-MS. In vivo, DGNTD therapy reduced pain, synovial inflammation, and fibrosis. The therapy significantly reduced levels of pain-related molecules, specifically calcitonin gene-related peptide (CGRP) and inducible nitric oxide synthase (iNOS), as well as fibrotic markers, including alpha smooth muscle actin (α-SMA) and type III collagen alpha-1 (Col3a1), in the synovium. A proteomics study demonstrated that DGNTD decreased the fibrotic protein Col3a1. DGNTD reduced the mRNA expression of pro-inflammatory and fibrotic markers (tumor necrosis factor alpha (TNF-α), interleukin-1 beta(IL-1β), interleukin-6(IL-6), α-SMA, Col3a1and TGF-β) in TGF-β-induced FLS. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and validation results revealed that DGNTD inhibits synovial fibrosis via the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (AKT) signaling pathway. DGNTD partially relieves pain, synovitis, and synovial fibrosis by regulating the PI3K/AKT pathway. These findings provide fresh information about the underlying mechanisms and successful therapy of OA, as well as a theoretical and experimental foundation for the clinical management of OA using DGNTD.

Identification and validation of up-regulated TNFAIP6 in osteoarthritis with type 2 diabetes mellitus

Lines of evidence have indicated that type 2 diabetes mellitus (T2DM) is an independent risk factor for osteoarthritis (OA) progression. However, the study focused on the relationship between T2DM and OA at the transcriptional level remains empty. We downloaded OA- and T2DM-related bulk RNA-sequencing and single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) dataset. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to screen out hub genes between OA and T2DM, and functional enrichment was done. Single-cell sequencing analysis was further used to screen key genes on OA and T2DM datasets. Rat chondrocytes and human articular cartilage were used to validate biomarkers among OA and T2DM. Sixty-eight hub genes were obtained, which were mainly enriched in the inflammatory response. We found that the hub gene TNFAIP6 is not only closely related to OA and T2DM but also a marker of prehypertrophic chondrocytes, which are closely related to the progression of OA. TNFAIP6 was found to be significantly elevated in CD14 + monocytes in T2DM patients, and this group of cells can promote inflammation. Validation on rat chondrocytes and human cartilage showed that TNFAIP6 was highly expressed in OA and further increased in the presence of T2DM or high glucose. Our study identified several characteristic modules and hub genes in the pathogenesis of T2DM-induced OA, which may facilitate further investigation of its molecular mechanisms. Up-regulated TNFAIP6 may contribute to OA in patients with T2DM by the recruitment of pro-inflammatory CD14 + monocytes in the OA synovium, which provides a potential target for the diagnosis and treatment of T2DM-associated OA.

ShK-modified UCMSCs Inhibit M1-Like Macrophage Polarization and Alleviate Osteoarthritis Progression via PI3K/Akt Axis.

The potassium channel Kv1.3 plays an important role in regulating immune cell functions in many inflammatory diseases whereas rarely in osteoarthritis (OA). Here, it is demonstrated that the Kv1.3 of macrophages is upregulated in response to LPS stimulation, as well as in human OA synovium samples than non-OA. Administration of Stichodactyla toxin (ShK), a Kv1.3 blocker, significantly inhibited cartilage degeneration and synovial inflammation in animal models of OA in vivo by inhibiting M1 macrophage polarization and reducing the production of inflammatory factors. In this study, a transgenically engineered human umbilical cord mesenchymal stem cell (UCMSC) delivery system is developed that secreted a peptide ShK, a Kv1.3 potassium blocker, into the knee articular cavity. Collectively, the results identified Kv1.3 as a potential therapeutic target for OA and demonstrated the efficacy of using ShK transgenic engineered UCMSCs as a delivery for the peptide in OA treatment.

Correlation of fecal microbiome dysregulation to synovial transcriptome in an equine model of obesity associated osteoarthritis.

Osteoarthritis (OA) is increasingly thought to be a multifactorial disease in which sustained gut inflammation serves as a continued source of inflammatory mediators driving degenerative processes at distant sites such as joints. The objective of this study was to use the equine model of naturally occurring obesity associated OA to compare the fecal microbiome in OA and health and correlate those findings to differential gene expression synovial fluid (SF) cells, circulating leukocytes and cytokine levels (plasma, SF) towards improved understanding of the interplay between microbiome and immune transcriptome in OA pathophysiology. Feces, peripheral blood mononuclear cells (PBMCs), and SF cells were isolated from healthy skeletally mature horses (n=12; 6 males, 6 females) and those with OA (n=6, 2 females, 4 males). Horses were determined to have OA via lameness evaluation, response to intra-articular (IA) diagnostic analgesia, and radiographic and arthroscopic evidence. Horses were excluded who had received medications or joint injections within 2 months. Cytokine analyses of plasma and SF were performed via multiplex immunoassay. Fecal bacterial microbial 16s DNA sequencing was performed and correlated to bulk RNA sequencing of SF cells and PBMC performed using an Illumina based platform. Horses with OA had higher body condition scores (P=0.009). Cytokines were elevated in plasma [interleukin (IL)-2, IL-6, IL-18, interferon gamma (IFN-γ), interferon gamma inducible protein 10 (CXCL10 or IP-10), granulocyte colony-stimulating factor (G-CSF)] and SF (IL-1β, IL-6, IL-17A, IL-18, IP-10, G-CSF) in OA. Microbial principal coordinate analysis (PCoA) using Bray-Curtis dissimilarity for β-diversity demonstrated distinct grouping of samples from OA versus healthy horses (P=0.003). Faith alpha diversity was reduced in OA (P=0.02). Analysis of microbiome composition showed differential relative abundance of taxa on multiple levels in OA. Specific phyla (Firmicutes, Verrucomicrobia, Tenericutes, Fibrobacteres), correlated to transcriptomic differences related to cell structure, extracellular matrix, collagen, laminin, migration, and motility, or immune response to inflammation in OA. These findings provide compelling evidence for a link between obesity, gut microbiome dysbiosis and differential gene expression in distant joint sites associated with development of OA in a relevant large animal model, establishing a connection here that provides a platform from which development of therapeutic interventions targeting the gut microbiome can build.

FSTL1 Can Be a Promising Target in TMJ Osteoarthritis via Regulating Chondrocyte Mitophagy and Apoptosis.

Previous studies have shown that follistatin-like protein 1 (FSTL1) is elevated in the synovial fluid of osteoarthritis and whether it is associated with disease development progress in cartilage degeneration is still unclear. The experiment was performed to explore the effect and mechanism of FSTL1 on chondrocyte degeneration and its further impaction in osteoarthritis as well as its treatment method. The patients who were diagnosed with temporomandibular joint (TMJ) disc displacement and osteoarthritis (OA) group was divided into 2 groups, anterior disc displacement (ADD) without bone resorption and ADD with bone resorption group according to the radiologic examination. The ELISA kit was used to determine the expression level of FSTL1 in patients TMJ environment. The function of FSTL1 in promoting chondrocyte degeneration was tested by quantitative reverse transcription polymerase chain reaction (Rt-qPCR) and western blot. The chondrocyte apoptosis and mitophagy were further test by flow cytometry and mitosox staining by upregulating and downregulating of FSTL1. In the end, the effectiveness of regulating FSTL1 in OA procedure was further validated by hematoxylin-eosin (HE), safranin O, and immunohistochemical (IHC) staining in vivo. There were 56 samples collected from the patients were included into this study. According to the ELISA results, FSTL1 expression levels of ADD without bone resorption groups were significantly lower than that in ADD with bone resorption group. Furthermore, the rate of cell apoptosis cells and the mitophagy procedure were highly activated when FSTL1 was upregulated. The morphology analysis of mitochondria showed significant changes when FSTL1 was highly upregulated in vitro. The in vivo and in vitro experiments showed that suppressing FSTL1 could alleviate the cartilage degeneration in TMJ OA progression. To sum up, upregulated expression level of FSTL1 in synovial fluid promoted the progression of TMJ OA by upregulating accelerating the chondrocyte apoptosis and mitophagy, and suppressing the FSTL1 in TMJ can rescue the OA progression. Therefore, it may be a promising result to consider the FSTL1 as a therapeutic target in the future.

Soufeng sanjie formula alleviates osteoarthritis by inhibiting macrophage M1 polarization and modulating intestinal metabolites

Ethnopharmacological relevanceOsteoarthritis (OA) is defined as “bone bi” disease based on clinical symptoms in Chinese medicine. Soufeng sanjie formula (SF) is a traditional formula for treating “bone bi” disease, which consists of Scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch) (0.5 g), Scorpions (dried body of Buthus martensii Karsch) (0.5 g), Astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge) (20 g) and Black soybean seed coats (seed coats of Glycine max (L.) Merr) (30 g), and it can be used to treat rheumatoid arthritis. Nonetheless, the potential of SF to postpone the advancement of OA and its underlying mechanisms remain unexplored. Aim of the studyThis study investigated whether SF could alleviate OA and the underlying mechanisms. Materials and methodsAnterior cruciate ligament transection (ACLT) was performed to establish an OA mice model. Mechanical pain and cold pain were assessed to evaluate changes in pain sensitivity in OA mice. Micro-CT was used to observe the microstructure and quantify the bone morphological parameters of knee joints. Safranin O-fast green staining was used to evaluate cartilage damage, and Osteoarthritis Research Society International (OARSI) scores were calculated. Immunohistochemistry was used to assess the expression of inflammatory factors in the synovium of OA mice following SF administration. Immunofluorescence analyzed the fraction of CD80 and iNOS positive regions in the synovium of knee joints. The effect of SF on macrophage M1 polarization was investigated using flow cytometry, western blot and quantitative PCR (qPCR) in vitro. Untargeted metabolomics was used to identify the differential metabolites associated with OA. ResultsSF-treatment markedly reduced the cartilage damage, lowered the OARSI score and downregulated the pain sensitivity in the OA mice. Secondly, SF decreased the expression of IL-6, IL-1β, and TNF-α in the OA synovium. SF also reduced the percentage of CD80 and iNOS in the synovium of the knee joint after ACLT surgery by immunofluorescence. Thirdly, SF inhibited the protein expression of iNOS and COX-2, decreased the percentage of CD80, and reduced the mRNA levels of IL-6, IL-1β, and TNF-α in BMDM cells. Furthermore, SF inhibited the macrophage M1 polarization-related AKT/NF-κB signaling pathway. Finally, untargeted metabolomics showed that SF effectively reduced the levels of intestinal metabolite 18-hydroxyoleic acid in OA mice. ConclusionOur results suggested that SF reduced pain symptoms and joint inflammation in mice with OA. Furthermore, SF inhibited synovial macrophage M1 polarization and modified the levels of the pro-inflammatory intestinal metabolite 18-hydroxyoleic acid in OA mice. Therefore, SF may be act as a potential Chinese medicine for the treatment of OA.

Matrikine stimulation of equine synovial fibroblasts and chondrocytes results in an in vitro osteoarthritis phenotype.

Osteoarthritis (OA) is a debilitating disease that impacts millions of individuals and has limited therapeutic options. A significant hindrance to therapeutic discovery is the lack of in vitro OA models that translate reliably to in vivo preclinical animal models. An alternative to traditional inflammatory cytokine models is the matrikine stimulation model, in which fragments of matrix proteins naturally found in OA tissues and synovial fluid, are used to stimulate cells of the joint. The objective of this study was to determine if matrikine stimulation of equine synovial fibroblasts and chondrocytes with fibronectin fragments (FN7-10) would result in an OA phenotype. We hypothesized that FN7-10 stimulation of equine articular cells would result in an OA phenotype with gene and protein expression changes similar to those previously described for human chondrocytes stimulated with FN7-10. Synovial fibroblasts and chondrocytes isolated from four horses were stimulated in monolayer culture for 6 or 18 h with 1 µM purified recombinant 42 kD FN7-10 in serum-free media. At the conclusion of stimulation, RNA was collected for targeted gene expression analysis and media for targeted protein production analysis. Consistent with our hypothesis, FN7-10 stimulation resulted in significant alterations to many important genes that are involved in OA pathogenesis including increased expression of IL-1β, IL-4, IL-6, CCL2/MCP-1, CCL5/RANTES, CXCL6/GCP-2, MMP-1, MMP-3, and MMP13. The results of this study suggest that the equine matrikine stimulation model of OA may prove useful for in vitro experiments leading up to preclinical trials.

Characterization of the single cell landscape in normal and osteoarthritic equine joints.

Osteoarthritis (OA) is a major source of pain and disability worldwide. Understanding of disease progression is evolving, but OA is increasingly thought to be a multifactorial disease in which the innate immune system plays a role in regulating and perpetuating low-grade inflammation. The aim of this study was to enhance our understanding of OA immunopathogenesis through characterization of the transcriptomic responses in OA joints, with the goal to facilitate the development of targeted therapies. Single-cell RNA sequencing (scRNA-seq) was completed on cells isolated from the synovial fluid of three normal and three OA equine joints. In addition to synovial fluid, scRNA-seq was also performed on synovium from one normal joint and one OA joint. Characterization of 28,639 cells isolated from normal and OA-affected equine synovial fluid revealed the composition to be entirely immune cells (CD45+) with 8 major populations and 26 subpopulations identified. In synovial fluid, we found myeloid cells (macrophage and dendritic cells) to be overrepresented and T cells (CD4 and CD8) to be underrepresented in OA relative to normal joints. Through subcluster and differential abundance analysis of T cells we further identified a relative overrepresentation of IL23R+ gamma-delta (γδ) T cells in OA-affected joints (a cell type we report to be enriched in gene signatures associated with T helper 17 mediated immunity). Analysis of an additional 17,690 cells (11 distinct cell type clusters) obtained from synovium of one horse led to the identification of an OA-associated reduction in the relative abundance of synovial macrophages, which contrasts with the increased relative abundance of macrophages in synovial fluid. Completion of cell-cell interaction analysis implicated myeloid cells in disease progression, suggesting that the myeloid-myeloid interactions were increased in OA-affected joints. Overall, this work provides key insights into the composition of equine synovial fluid and synovium in health and OA. The data generated in this study provides equine-specific cell type gene signatures which can be applied to future investigations. Furthermore, our analysis highlights the potential role of macrophages and IL23R+ γδ T cells in OA immunopathogenesis.

Small extracellular vesicles derived from synovial fibroblasts contain distinct miRNA profiles and contribute to chondrocyte damage in osteoarthritis

BackgroundSmall extracellular vesicles (sEV) derived from synovial fibroblasts (SF) represent a novel molecular mechanism regulating cartilage erosion in osteoarthritis (OA). However, a comprehensive evaluation using disease relevant cells has not been undertaken. The aim of this study was to isolate and characterise sEV from OA SF and to look at their ability to regulate OA chondrocyte effector responses relevant to disease. Profiling of micro (mi) RNA signatures in sEV and parental OA SF cells was performed.MethodsSF and chondrocytes were isolated from OA synovial membrane and cartilage respectively (n = 9). sEV were isolated from OA SF (± IL-1β) conditioned media by ultracentrifugation and characterised using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Particle size was confirmed by nanoparticle tracking analysis (NTA). sEV regulation of OA chondrocyte and cartilage effector response was evaluated using qPCR, ELISA and sulphated glycosaminoglycan assay (sGAG). RNA-sequencing was used to establish miRNA signatures in isolated sEV from OA SF.ResultsOA SF derived sEV were readily taken up by OA chondrocytes, with increased expression of the catabolic gene MMP 13 (p < 0.01) and decreased expression of the anabolic genes aggrecan and COL2A1 (p < 0.01) observed. Treatment with sEV derived from IL-1β stimulated OA SF significantly decreased expression of aggrecan and COL2A1 (p < 0.001) and increased SOX 9 gene expression (p < 0.05). OA chondrocytes cultured with sEV from either non-stimulated or IL-1β treated OA SF, resulted in a significant increase in the secretion of IL-6, IL-8 and MMP-3 (p < 0.01). Cartilage explants cultured with sEV from SF (± IL-1β) had a significant increase in the release of sGAG (p < 0.01). miRNA signatures differed between parental SF cells and isolated sEV. The recently identified osteoclastogenic regulator miR182, along with miR4472-2, miR1302-3, miR6720, miR6087 and miR4532 were enriched in sEV compared to parental cells, p < 0.01. Signatures were similar in sEVs derived from non-stimulated or IL-1β stimulated SF.ConclusionsOA SF sEV regulate chondrocyte inflammatory and remodelling responses. OA SF sEV have unique signatures compared to parental cells which do not alter with IL-1β stimulation. This study provides insight into a novel regulatory mechanism within the OA joint which could inform future targeted therapy.

Degradomics defines proteolysis information flow from human knee osteoarthritis cartilage to matched synovial fluid and the contributions of secreted proteases ADAMTS5, MMP13 and CMA1 to articular cartilage breakdown

ObjectivesProteolytic cartilage extracellular matrix breakdown is a major mechanism of articular cartilage loss in osteoarthritis (OA) pathogenesis. We sought to determine the overlap of proteolytic peptides in matched knee OA cartilage and synovial fluid on a proteome-wide scale to increase the prospective biomarker repertoire and to attribute proteolytic cleavages to specific secreted proteases. DesignMatched human knee OA cartilage and synovial fluid (n=5) were analyzed by N-terminomics using Terminal Amine Isotopic Labeling of Substrates (TAILS), comprising labeling and enrichment of protein N-termini, high-resolution mass spectrometry and positional peptide mapping. Donor non-OA articular cartilage was digested with CMA1, MMP13 or ADAMTS5, and TAILS was used to identify cleavage sites, which were matched against cartilage and synovial fluid degradomes. ResultsOf over 20,000 cleaved peptides in the combined OA cartilage and synovial fluid degradomes, 677 peptides, originating from 153 proteins, were present in all cartilage and synovial fluid samples. CMA1, MMP13 and ADAMTS5 digestion of cartilage identified numerous cleavage sites for each protease and distinct cleavage site preferences. Peptides resulting from the activities of these proteases were detected in OA cartilage and synovial fluid. ConclusionsProteolytic fragments from both cartilage and circulating proteins are detectable by synovial fluid degradomics. CMA1, MMP13 and ADAMTS5 activity profiles in cartilage are distinct from each other and the previously determined HtrA1 profile. This work expands the proteolytic biomarker space for OA investigation, suggests that multiple, diverse proteases contribute to cartilage destruction, and demonstrates that their specific contributions can each be defined by multiple biomarkers.

Synovial expression of glucocorticoid receptor parallels fibroblast activation in patients with rheumatoid arthritis.

Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium. We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28). GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11β-HSD1/11β-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including 'inflammatory response', 'IFN-γ response' and 'IL6/JAK/STAT3 signalling'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state. GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.

Prof Analysis of CXCL12 and S100A12 levels in peripheral blood and synovial fluid and their correlation with severity in patients with knee osteoarthritis

Abstract: To investigate the expression of CXCL12 and S100A12 in peripheral blood (PB) and synovial fluid (SF) of patients with knee osteoarthritis (OS) and to analyze the correlation between them and the severity of knee OS. 60 patients with kneeOS treated in our hospital from January 2020 to December 2022 were selected as the experimental group, and 60 healthy knee joints with similar age were selected as the control group. The fasting venous blood of 120 subjects was drawn in the early morning, and the SF was extracted during joint operation or sodium hyaluronate injection. Put the collected PB and SF in the refrigerator at-80℃. The levels of CXCL12 and S100A12 in PB and SF were detected by enzyme linked immunosorbent assay (Elisa). The correlation between the levels of CXCL12 and S100A12 in PB and SF and Kmurl L grade and WOMAC score. The levels of CXCL12 and S100A12 in PB and SF in the observation group were raised than those in the control group. There were significant differences in the levels of CXCL12 and S100A12 in PB and SF in the experimental group. The higher the Kmurl grade of knee OS, the higher the concentration of CXCL12 and S100A12 in PB and SF. The levels of CXCL12 and S100A12 in PB of knee OS were positively correlated with WOMAC score (r = 0.767, 0.521 respectively, P &lt; 0.05), see figure 1. The levels of CXCL12 and S100A12 in SF of knee OS were positively correlated with WOMAC score (r = 0.663, 0.357 respectively, P &lt; 0.05). The levels of CXCL12 and S100A12 in PB and SF are positively correlated with the severity of knee OS. The levels of CXCL12 and S100A12 in PB and SF can provide basis for the evaluation and prognosis of knee OS.

A novel method to quantify TSG‐6 protein levels in synovial fluid from osteoarthritis patients

AbstractTSG‐6, the protein product of Tumor Necrosis Factor‐stimulated gene‐6, is a potential biomarker of disease activity/progression in osteoarthritis (OA). By ELISA, TSG‐6 is elevated in synovial fluid (SF) from OA patients and its catalytic activity, for the covalent transfer of inter‐α‐inhibitor heavy chains onto hyaluronan (HA), is reported to correlate with progression to total knee replacement. Here, quantitative western blot (qWB) analysis, following sequential digestion with hyaluronidase and chondroitinase enzymes, was developed for the accurate determination of TSG‐6 levels in SFs. qWB analysis of 125 OA SFs yielded values of 1.0–45.2 μg/mL (median: 3.9 μg/mL), 100–1000‐fold higher than those previously reported; TSG‐6 concentration was positively correlated with age and pain/outcome scores in male patients. The values determined, by ELISA or a heavy chain transfer activity assay, following the same digestion conditions (in 23 SFs), were both ≥10‐fold lower. Apparent TSG‐6 catalytic activity was significantly affected by the concentration of HA present in SF or added exogenously. Thus, the interactions of TSG‐6 with components of OA SF prevent accurate determination of its concentration/activity when using existing assays. However, the quantitative western blot method developed here appears more suitable for further evaluation of the utility of TSG‐6 as a biomarker in OA.

Bibliometric analysis of synovial in osteoarthritis in the last 10 years

BackgroundOur aim was to examine trends in the bibliometric analysis of synovial for osteoarthritis over the last 10 years. MethodsPublications relevant to synovial in osteoarthritis from 2013 to 2022 were retrieved from the Science Citation Index Expanded (SCI-E), Social Sciences Citation Index (SSCI), and Web of Science Core Collection (WoSCC) databases. The countries/regions, institutions, authors, journals, references, and keywords related to this topic were extracted using Citespace and Vosviewer. Citespace and Vosviewer were also used to identify and analyze this field's research hotspots and trends. ResultsOver the past 10 years, 5738 articles addressing the role of synovium in osteoarthritis have been published. Between 2013 and 2022, 2021 had the highest amount of published articles (a total of 756 published articles, or 13.18 % of the total articles) covering synovial in osteoarthritis. China was the country that published the most articles, while Duke University was the institution that published the most articles. Osteoarthritis and Cartilage was the journal with the most publications related to the study of Synovium in osteoarthritis. The National Nature Science Foundation of China provided the most funding. According to the analysis of keyword burst detection, human cartilage, control experiment, and exosomes were the most searched at different points in time. ConclusionIn the last ten years, both the number of citations and the article discussing synovial in osteoarthritis have increased. The top 10 most searched keywords were “osteoarthritis","synovial fluid”, “inflammation”, “cartilage”, “expression","rheumatoid arthritis","articular cartilage”, “knee osteoarthritis”, “synovial”, “knee". According to the timeline view of co-citation clustering, synovial components and their expressions have emerged as hotspots of research associated with synovial osteoarthritis.

Comprehensive Analysis of Sphingolipid Metabolism-Related Genes in Osteoarthritic Diagnosis and Synovial Immune Dysregulation.

BACKGROUND Osteoarthritis (OA) is a chronic degenerative disease characterized by synovitis and has been implicated in sphingolipid metabolism disorder. However, the role of sphingolipid metabolism pathway (SMP)-related genes in the occurrence of OA and synovial immune dysregulation remains unclear. MATERIAL AND METHODS In this study, we obtained synovium-related databases from GEO (n=40 for both healthy controls and OA) and analyzed the expression levels of SMP-related genes. Using 2 algorithms, we identified hub genes and developed a diagnostic model incorporating these hub genes to predict the occurrence of OA. Subsequently, the hub genes were further validated in peripheral blood samples from OA patients. Additionally, CIBERSORT and MCP-counter analyses were employed to explore the correlation between hub genes and immune dysregulation in OA synovium. WGCNA was used to determine enriched modules in different clusters. RESULTS Overall, the expression levels of SMP genes were upregulated in OA synovium. We identified 6 hub genes of SMP and constructed an excellent diagnostic model (AUC=0.976). The expression of re-confirmed hub genes showed associations with immune-related cell infiltration and levels of inflammatory cytokines. Furthermore, we observed heterogeneity in the expression patterns of hub genes across different clusters of OA. Notably, older patients displayed increased susceptibility to elevated levels of pain-related inflammatory cytokines and infiltration of immune cells. CONCLUSIONS The SMP-related hub genes have the potential to serve as diagnostic markers for OA patients. Moreover, the 4 hub genes of SMP demonstrate wide participation in immune dysregulation in OA synovium. The activation of different pathways is observed among different populations of patients with OA.

Advances in viscosupplementation and tribosupplementation for early-stage osteoarthritis therapy.

Joint kinematic instability, arising from congenital or acquired musculoskeletal pathoanatomy or from imbalances in anabolism and catabolism induced by pathophysiological factors, leads to deterioration of the composition, structure and function of cartilage and, ultimately, progression to osteoarthritis (OA). Alongside articular cartilage degeneration, synovial fluid lubricity decreases in OA owing to a reduction in the concentration and molecular weight of hyaluronic acid and surface-active mucinous glycoproteins that form a lubricating film over the articulating joint surfaces. Minimizing friction between articulating joint surfaces by lubrication is fundamental for decreasing hyaline cartilage wear and for maintaining the function of synovial joints. Augmentation with highly viscous supplements (that is, viscosupplementation) offers one approach to re-establishing the rheological and tribological properties of synovial fluid in OA. However, this approach has varied clinical outcomes owing to limited intra-articular residence time and ineffective mechanisms of chondroprotection. This Review discusses normal hyaline cartilage function and lubrication and examines the advantages and disadvantages of various strategies for restoring normal joint lubrication. These strategies include contemporary viscosupplements thatcontain antioxidants, anti-inflammatory drugs or platelet-rich plasma and new synthetic synovial fluid additives and cartilage matrix enhancers. Advanced biomimetic tribosupplements offer promise for mitigating cartilage wear, restoring joint function and, ultimately, improving patient care.

Cartilage oligomeric matrix protein as a potential biomarker for knee osteoarthritis.

This study aimed to determine the expression and clinical significance of a cartilage protein, cartilage oligomeric matrix protein (COMP), in knee osteoarthritis (OA) patients. A total of 270 knee OA patients and 93 healthy controls were recruited. COMP messenger RNA (mRNA) and protein levels in serum, synovial fluid, synovial tissue, and fibroblast-like synoviocytes (FLSs) of knee OA patients were determined using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry. COMP protein levels were significantly elevated in serum and synovial fluid of knee OA patients, especially those in the advanced stages of the disease. Serum COMP was significantly correlated with radiological severity as well as measures of body composition, physical performance, knee pain, and disability. Receiver operating characteristic curve analysis unveiled a diagnostic value of serum COMP as a biomarker of knee OA (41.64 ng/ml, area under the curve (AUC) = 1.00), with a sensitivity of 99.6% and a specificity of 100.0%. Further analysis uncovered that COMP mRNA expression was markedly upregulated in the inflamed synovium of knee OA, consistent with immunohistochemical staining revealing localization of COMP protein in the lining and sub-lining layers of knee OA inflamed synovium. Most notably, relative COMP mRNA expression in knee OA synovium was positively associated with its protein levels in serum and synovial fluid of knee OA patients. In human knee OA FLSs activated with tumour necrosis factor-alpha, COMP mRNA expression was considerably up-regulated in a time-dependent manner. All results indicate that COMP might serve as a supportive diagnostic marker for knee OA in conjunction with the standard diagnostic methods.

Investigating protease-mediated peptides of inflammation and tissue remodeling as biomarkers associated with flares in psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. PsA disease involves flares, which are associated with increased joint inflammation and tissue remodeling. There is a need for identifying biomarkers related to PsA disease activity and flares to improve the management of PsA patients and decrease flares. The tissue turnover imbalance that occurs during the inflammatory and fibro-proliferative processes during flares leads to an increased degradation and/or reorganization of the extracellular matrix (ECM), where increased proteolysis plays a key role. Hence, protease-mediated fragments of inflammatory and tissue-remodeling components could be used as markers reflecting flares in PsA patients. A broad panel of protease-mediated biomarkers reflecting inflammation and tissue remodeling was measured in serum and synovial fluid (SF) obtained from PsA patients experiencing flares (acutely swollen joint[s], PsA-flare). In serum, biomarker levels assessed in PsA-flare patients were compared to controls and in early-diagnosed PsA patients not experiencing flares (referred to as PsA without flare). Furthermore, the biomarker levels assessed in SF from PsA-flare patients were compared to the levels in SF of osteoarthritis (OA) patients. In serum, levels of the PRO-C3 and C3M, reflecting formation and degradation of the interstitial matrix, were found significantly elevated in PsA-flare compared to controls and PsA without flare. The remodeling marker of the basement membrane, PRO-C4, was significantly elevated in PsA-flare compared to PsA without flare. The inflammation and immune cell activity related markers, CRPM, VICM, and CPa9-HNE were significantly elevated in PsA-flare patients compared to controls and PsA without flare. In addition, VICM (AUC = 0.71), CPa9-HNE (AUC = 0.89), CRPM (AUC = 0.76), and PRO-C3 (AUC = 0.86) showed good discriminatory performance for separating PsA-flare from PsA without flare. In SF, the macrophage activity marker, VICM, was significantly elevated whereas the type II collagen formation marker, PRO-C2, was significantly reduced in the PsA-flare compared to OA. The combination of five serum markers reflecting type III and IV collagen degradation (C3M and C4M, respectively), type III and VI collagen formation (PRO-C3 and PRO-C6, respectively), and neutrophil activity (CPa9-HNE) showed an excellent discriminatory performance (AUC = 0.98) for separating PsA-flare from PsA without flares. The serum biomarker panel of C3M, C4M, PRO-C3, PRO-C6, and CPa9-HNE reflecting synovitis, enthesitis, and neutrophil activity may serve as novel tool for quantitatively monitoring flares in PsA patients.

Correlation of the total superoxide dismutase activity between joint fluid and synovium in end-stage knee osteoarthritis.

Recently, we found significantly reduced total superoxide dismutase (SOD) activity in the cartilage of patients with end-stage knee osteoarthritis (OA). In this study, we aimed to evaluate the SOD activity in serum, joint fluid, cartilage, and synovial membrane samples collected from 52 patients with end-stage knee OA who underwent total knee arthroplasty. The relationship between the total SOD activity in each tissue was evaluated using Spearman's rank correlation coefficient. The joint fluid total SOD activity was used as the objective variable, and its association with the serum, cartilage, and synovial total SOD activities was evaluated using multiple linear regression analysis. Univariate analysis revealed that joint fluid total SOD activity was positively correlated with synovial total SOD activity. Multiple linear regression analysis using joint fluid total SOD activity as the objective variable showed a positive association with synovial total SOD activity (β = 0.493, adjusted R2 = 0.172, P < 0.01). In patients with end-stage knee OA, the state of the synovial total SOD activity is better reflected by the total SOD activity in the joint fluid than that in the cartilage. Joint fluid total SOD activity may serve as a biomarker for the treatment and prevention of synovitis.

Discovery of calcite as a new pro-inflammatory calcium-containing crystal in human osteoarthritic synovial fluid

ObjectiveWe aimed to characterize calcium-containing crystals present in synovial fluid from patients with knee osteoarthritis (OA) using Raman spectroscopy, and specifically investigate the biological effects of calcite crystals. DesignThirty-two synovial fluid samples were collected pre-operatively from knee OA patients undergoing total joint arthroplasty. An integrated Raman polarized light microscope was used for identification of crystals in synovial fluid. Human peripheral-blood mononuclear cells (PBMC’s), human OA articular chondrocytes (HACs) and fibroblast-like synoviocytes (FLSs) were exposed to calcite crystals. Expression of relevant cytokines and inflammatory genes were measured using ELISA and real-time PCR. ResultsVarious calcium-containing crystals were identified, including calcium pyrophosphate (37.5%) and basic calcium phosphate (21.8%), but they were never found simultaneously in the same OA synovial fluid sample. For the first time, we discovered the presence of calcite crystals in 93.8% of the samples, while dolomite was detected in 25% of the cases. Characterization of the cellular response to calcite crystal exposure revealed increased production of innate immune-derived cytokines by peripheral blood mononuclear cells (PBMC’s), when co-stimulated with lipopolysaccharide (LPS). Additionally, calcite crystal stimulation of HACS and FLSs resulted in enhanced secretion of pro-inflammatory molecules and alterations in the expression of extracellular matrix remodeling enzymes. ConclusionsThis study highlights the unique role of Raman spectroscopy in OA crystal research and identified calcite as a novel pro-inflammatory crystal type in OA synovial fluid. Understanding the role of specific crystal species in the OA joint may open new avenues for pharmacological interventions and personalized approaches to treating OA.