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Autoimmunity underlies many painful disorders, such as enthesopathies, which localize to the enthesis. From infiltration of the synovium and axial skeleton by B cells, to disturbances in the ratio of M1/M2 enthesis macrophages, to CD8 + T cell mediated inflammation, autoimmune dysregulation is becoming increasingly well characterized in enthesopathies. Tissue resident B cells, macrophages, neutrophils, and T cells have also been localized in healthy human entheses. However, the potential developmental origins, presence, and role of immune cells (ICs) in enthesis development is not known. Here, we use single-cell RNA-sequencing analysis to describe IC subtypes present in the enthesis before, during, and after mineralization, and to infer regulatory interactions between ICs and mesenchymal cells (MCs). We report the presence of nine phenotypically distinct IC subtypes, including B cells, macrophages, neutrophils, and T cells. We find that specific IC subtypes may promote MC-proliferation and differentiation, and that MCs may regulate IC phenotype and autoimmunity. Our findings suggest that bidirectional regulatory interactions between ICs and MCs may be important to enthesis mineralization, and suggest that progenitor MCs have a unique ability to limit autoimmunity during development. [ABSTRACT FROM AUTHOR]

Objectives: 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. Methods: 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. Results: 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). Conclusion: 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 microvessels in 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. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetric polyarthritis. RA is routinely treated by various systemic drugs; on the other hand, administration of intra-articular corticosteroids or different types of synovectomies can be used in case of systemic medication's failure. Chemical, radio isotopic, and surgical synovectomies are being used as therapeutic options for chronic synovitis to improve joint function. Chemical synovectomy is not well tolerated, and the long-term response is relatively low. Surgical synovectomy has a better success rate, but it recommends higher expenses. In radiation synovectomy, radioactive labeled particles are applied directly in the articular cavity, followed by homogeneous distribution in joint. Next, the radioactive particles are transported in the depth of synovia and phagocytized by inflammatory cells. Finally, the radiation leads to fibrosis and sclerosis of formerly inflamed synovial membrane; thus, it stops the inflammation and reduces the symptoms. It has a success rate of 40–100% and its effect can be similar to surgical synovectomy. Materials and methods: Thirty-one patients with resistant monoarthritis of the knee were enrolled in this study. One millicurie of phosphorus-32 was injected into patients' knee via US guide. Saline was injected afterwards to prevent leakage. Direct pressure was performed after removing the needle and the knee was flexed slowly to ensure homogenous distribution and fixed with a splint for 1 to 2 weeks. Patients were followed up after 2 weeks, 1 month, 2 months, and 6 months. The following variables were assessed by the treating rheumatologist: patients' pain, joint tenderness, effusion, and ROM. At the time of injection and after the first week, patients were investigated for any complication including infection, necrosis, pain, and swelling. The effect of clinical characteristics and demographic data on existing complications and the changes of pain, joint tenderness, effusion, and ROM was assessed. Results: Thirty-one patients with the mean age of 54.5 ± 12.2 years and the mean disease duration of 12 ± 6.5 years were enrolled in this study. Mean DAS-28 ESR score for our patients was 4 ± 0.7. The pain, effusion, and reduced ROM were decreased significantly after all follow-up intervals. Knee tenderness was not affected in the first 2 weeks, but it was reduced significantly after 1, 2, and 6 months. No serious complications like infection and necrosis were reported through our study. 51.6% and 54.8% of our patients reported pain and swelling in the administration site. Furthermore, 19.4% and 16.1% of patients reported deterioration of pain and effusion in the first week of injection. Conclusion: In our study, we demonstrated that pain, tenderness, effusion, and ROM are improved after radiation synovectomy with phosphorus-32. We also showed that there was no serious adverse effect like infection and necrosis. However, more than half of our patients experienced pain and swelling of injection site at the time of administration. Key points • We demonstrated the efficacy of radiation synovectomy as a medication for monoarthritis. • The results of our study can lead to a bigger clinical trial to assess the benefits and adverse effects of radiation synovectomy in comparison to treatment with local or systemic corticosteroids. [ABSTRACT FROM AUTHOR]

Synovial chondromatosis (SC) is a disorder of the synovium characterized by the formation of osteochondral nodules within the synovium. This study aimed to identify the abnormally differentiated progenitor cells and possible pathogenic signaling pathways. Loose bodies and synovium were obtained from patients with SC during knee arthroplasty. Single-cell RNA sequencing was used to identify cell subsets and their gene signatures in SC synovium. Cells derived from osteoarthritis (OA) synovium were used as controls. Multi-differentiation and colony-forming assays were used to identify progenitor cells. The roles of transcription factors and signaling pathways were investigated through computational analysis and experimental verification. We identified an increased proportion of CD34+ sublining fibroblasts in SC synovium. CD34+CD31− cells and CD34−CD31− cells were sorted from SC synovium. Compared with CD34− cells, CD34+ cells had larger alkaline phosphatase (ALP)-stained area and calcified area after osteogenic induction. In addition, CD34+ cells exhibited a stronger tube formation ability than CD34− cells. Our bioinformatic analysis suggested the expression of TWIST1, a negative regulator of osteogenesis, in CD34− sublining fibroblasts and was regulated by the TGF-β signaling pathway. The experiment showed that CD34+ cells acquired the TWIST1 expression during culture and the combination of TGF-β1 and harmine, an inhibitor of Twist1, could further stimulate the osteogenesis of CD34+ cells. Overall, CD34+ synovial fibroblasts in SC synovium have multiple differentiation potentials, especially osteogenic differentiation potential, and might be responsible for the pathogenesis of SC. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA. Activated B cells and T cells accumulate within joints of patients with rheumatoid arthritis. Here, the authors use single-cell transcriptome and repertoire profiling to identify clonally expanded synovial B cells and T cells and define their phenotypes and predicted cell-cell interactions. [ABSTRACT FROM AUTHOR]

One of the most common musculoskeletal disorders, osteoarthritis (OA), causes worldwide disability, morbidity, and poor quality of life by degenerating articular cartilage, modifying subchondral bone, and inflaming synovial membranes. OA pathogenesis pathways must be understood to generate new preventative and disease-modifying therapies. In recent years, it has been acknowledged that gut microbiota (GM) can significantly contribute to the development of OA. Dysbiosis of GM can disrupt the "symphony" between the host and the GM, leading to a host immunological response that activates the "gut–joint" axis, ultimately worsening OA. This narrative review summarizes research supporting the "gut–joint axis" hypothesis, focusing on the interactions between GM and the immune system in its two main components, innate and adaptive immunity. Furthermore, the pathophysiological sequence of events that link GM imbalance to OA and OA-related pain is broken down and further investigated. We also suggest that diet and prebiotics, probiotics, nutraceuticals, exercise, and fecal microbiota transplantation could improve OA management and represent a new potential therapeutic tool in the light of the scarce panorama of disease-modifying osteoarthritis drugs (DMOADs). Future research is needed to elucidate these complex interactions, prioritizing how a particular change in GM, i.e., a rise or a drop of a specific bacterial strain, correlates with a certain OA subset to pinpoint the associated signaling pathway that leads to OA. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of isorhamnetin on the pathology of rheumatoid arthritis (RA). Methods: Tumor necrosis factor (TNF)- α -induced fibroblast-like synoviocytes (FLS) was exposed to additional isorhamnetin (10, 20 and 40 µ mol/L). Overexpression vectors for matrix metalloproteinase-2 (MMP2) or MMP9 or SRC were transfected to explore their roles in isorhamnetin-mediated RA-FLS function. RA-FLS viability, migration, and invasion were evaluated. Moreover, a collagen-induced arthritis (CIA) rat model was established. Rats were randomly divided to sham, CIA, low-, medium-, and high-dosage groups using a random number table (n=5 in each group) and administed with normal saline or additional isorhamnetin [2, 10, and 20 mg/(kg·day)] for 4 weeks, respectively. Arthritis index was calculated and synovial tissue inflammation was determined in CIA rats. The levels of MMP2, MMP9, TNF-α, interleukin-6 (IL-6), and IL-1 β, as well as the phosphorylation levels of SRC, extracellular regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding (CREB), were detected in RA-FLS and synovial tissue. Molecular docking was also used to analyze the binding of isorhamnetin to SRC. Results: In in vitro studies, isorhamnetin inhibited RA-FLS viability, migration and invasion (P<0.05). Isorhamnetin downregulated the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β in RA-FLS (P<0.05). The overexpression of either MMP2 or MMP9 reversed isorhamnetin-inhibited RA-FLS migration and invasion, as well as the levels of TNF-α, IL-6, and IL-1 β (P<0.05). Furthermore, isorhamnetin bound to SRC and reduced the phosphorylation of SRC, ERK, and CREB (P<0.05). SRC overexpression reversed the inhibitory effect of isorhamnetin on RA-FLS viability, migration and invasion, as well as the negative regulation of MMP2 and MMP9 (P<0.05). In in vivo studies, isorhamnetin decreased arthritis index scores (P<0.05) and alleviated synovial inflammation. Isorhamnetin reduced the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β, as well as the phosphorylation of SRC, ERK, and CREB in synovial tissue (P<0.05). Notably, the inhibitory effect of isorhamnetin was more pronounced at higher concentrations (P<0.05). Conclusion: Isorhamnetin exhibited anti-RA effects through modulating SRC/ERK/CREB and MMP2/MMP9 signaling pathways, suggesting that isorhamnetin may be a potential therapeutic agent for RA. [ABSTRACT FROM AUTHOR]

The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception. [ABSTRACT FROM AUTHOR]

The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression. Hundreds of arthritis-associated genetic variants have been identified but in most cases their functions remain unknown. Here the authors develop a resource to reveal the effects of variants on gene expression in human synovium, and identify arthritis-related genes. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a progressive cartilage degradation disease, concomitant with synovitis, osteophyte formation, and subchondral bone sclerosis. Over 37% of the elderly population is affected by OA, and the number of cases is increasing as the global population ages. Therefore, the objective of this study was to identify and analyze the hub genes of OA combining with comprehensive bioinformatics analysis tools to provide theoretical basis in further OA effective therapies. Two sample sets of GSE46750 contained 12 pairs OA synovial membrane and normal samples harvested from patients as well as GSE98918 including 12 OA and non-OA patients were downloaded from the Gene Expression Omnibus database (GEO) database. Differentially expressed genes (DEGs) were identified using Gene Expression Omnibus 2R (GEO2R), followed by functional enrichment analysis, protein–protein interaction networks construction. The hub genes were identified and evaluated. An OA rat model was constructed, hematoxylin and eosin staining, safranin O/fast green staining, cytokines concentrations of serum were used to verify the model. The hub genes expression level in the knee OA samples were verified using RT-qPCR. The top 20 significantly up-regulated and down-regulated DEGs were screened out from the two datasets, respectively. The top 18 GO terms and 10 KEGG pathways were enriched. Eight hub genes were identified, namely MS4A6A, C1QB, C1QC, CD74, CSF1R, HLA-DPA1, HLA-DRA and ITGB2. Among them, the hub genes were all up-regulated in in vivo OA rat model, compared with healthy controls. The eight hub genes identified (MS4A6A, C1QB, C1QC, CD74, CSF1R, HLA-DPA1, HLA-DRA and ITGB2) were shown to be associated with OA. These genes can serve as disease markers to discriminate OA patients from healthy controls. [ABSTRACT FROM AUTHOR]

Preoperative hemorrhage can be reduced using anti-fibrinolytic medicine tranexamic acid (TXA). During surgical procedures, local administration is being used more and more frequently, either as an intra-articular infusion or as a perioperative rinse. Serious harm to adult soft tissues can be detrimental to the individual since they possess a weak ability for regeneration. Synovial tissues and primary fibroblast-like synoviocytes (FLS) isolated from patients were examined using TXA treatment in this investigation. FLS is obtained from rheumatoid arthritis (RA), osteoarthritis (OA), and anterior cruciate ligament (ACL)-ruptured patients. The in vitro effect of TXA on primary FLS was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays for cell death, annexin V/propidium iodide (PI) staining for apoptotic rate, real-time PCR for p65 and MMP-3 expression, and enzyme-linked immunosorbent assay (ELISA) for IL-6 measurement. MTT assays revealed a significant decrease in cell viability in FLS of all groups of patients following treatment with 0.8-60 mg/ml of TXA within 24 h. There was a significant increase in cell apoptosis after 24 h of exposure to TXA (15 mg/ml) in all groups, especially in RA-FLS. TXA increases the expression of MMP-3 and p65 expression. There was no significant change in IL-6 production after TXA treatment. An increase in receptor activator of nuclear factor kappa-Β ligand (RANK-L) production was seen only in RA-FLS. This study demonstrates that TXA caused significant synovial tissue toxicity via the increase in cell death and elevation of inflammatory and invasive gene expression in FLS cells. [ABSTRACT FROM AUTHOR]

For knee osteoarthritis and related conditions, analysis of biomarkers hold promise to improve early diagnosis and/or offer patient-specific treatment. To compare biomarker analyses, reliable, high-quality biopsies are needed. The aim of this work is to summarize the literature on the current best practices of biopsy of the synovium and synovial fluid arthrocentesis. Therefore, PubMed, Embase and Web of Science were systematically searched for articles that applied, demonstrated, or evaluated synovial biopsies or arthrocentesis. Expert recommendations and applications were summarized, and evidence for superiority of techniques was evaluated. Thirty-one studies were identified for inclusion. For arthrocentesis, the superolateral approach in a supine position, with a 0°-30° knee flexion was generally recommended. 18-gage needles, mechanical compression and ultrasound-guidance were found to give superior results. For blind and image-guided synovial biopsy techniques, superolateral and infrapatellar approaches were recommended. Single-handed tools were preconized, including Parker-Pearson needles and forceps. Sample quantity ranged approximately from 2 to 20. Suggestions were compiled for arthrocentesis regarding approach portal and patient position. Further evidence regarding needle size, ultrasound-guidance and mechanical compression were found. More comparative studies are needed before evidence-based protocols can be developed. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease. [ABSTRACT FROM AUTHOR]

Purpose: Aim of this systematic review was to determine if bone marrow-derived cell-based injectable therapies induce disease-modifying effects in joints affected by osteoarthritis (OA) in animal models. Methods: A systematic review was performed on three electronic databases (PubMed, Web of Science, Embase) according to PRISMA guidelines. A synthesis of the results was performed investigating disease-modifying effects in preclinical animal studies comparing injectable bone marrow-derived products with OA controls or other products, different formulations or injection intervals, and the combination with other products. The risk of bias was assessed according to the SYRCLE's tool. Results: Fifty-three studies were included (1819 animals) with an increasing publication trend over time. Expanded cells were used in 48 studies, point-of-care products in 3 studies, and both approaches were investigated in 2 studies. Among the 47 studies presenting results on the disease-modifying effects, 40 studies (85%) reported better results with bone marrow-derived products compared to OA controls, with positive findings evident in 14 out of 20 studies (70%) in macroscopic assessment, in 30 out of 41 studies (73%) in histological assessment, and in 10 out of 13 studies (77%) in immunohistochemical evaluations. Clinical evaluations showed positive results in 7 studies out of 9 (78%), positive imaging results in 11 studies out of 17 (65%), and positive biomarker results in 5 studies out of 10 (50%). While 36 out of 46 studies (78%) reported positive results at the cartilage level, only 3 out of 10 studies (30%) could detect positive changes at the synovial level. The risk of bias was low in 42% of items, unclear in 50%, and high in 8%. Conclusion: This systematic review of preclinical studies demonstrated that intra-articular injections of bone marrow-derived products can induce disease-modifying effects in the treatment of OA, slowing down the progression of cartilage damage with benefits at macroscopic, histological, and immunohistochemical levels. Positive results have been also observed in terms of clinical and imaging findings, as well as in the modulation of inflammatory and cartilage biomarkers, while poor effects have been described on the synovial membrane. These findings are important to understand the potential of bone marrow-derived products and to guide further research to optimise their use in the clinical practice. Level of evidence: II. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools. [ABSTRACT FROM AUTHOR]

This article discusses two rare cases of intra-labral pigmented villonodular synovitis (PVNS) of the hip. The hip joint represents the second most common location of pigmented villonodular synovitis, second to the knee [1]. The majority of hip PVNS cases either diffusely involve the synovium or are focal lesions within the joint. The lesions and synovium show foci of low signal intensity related to hemosiderin deposition, a finding that differentiates PVNS from other causes of synovial proliferation. Our case report presents two rare manifestations of PVNS lesions localized within the hip labrum. This presentation could easily be mistaken for a cyst by imaging modality. Despite the rarity of this condition, we highlight the importance of questioning the possibility of intra-labral PVNS, when patients have persistent hip pain not responding to therapy and atypical imaging findings. Highlighting this rare presentation is crucial for establishing the correct diagnosis, guiding treatment, and obtaining the best clinical outcome. [ABSTRACT FROM AUTHOR]

The inner surface layer of human joints, the synovium, is a source of stem cells for the repair of articular cartilage defects. We investigated the potential of the normal human synovium to form novel cartilage and compared its chondrogenic capacity with that of two patient groups suffering from major joint diseases: young adults with femoro-acetabular impingement syndromes of the hip (FAI), and elderly individuals with osteoarthritic degeneration of the knee (OA). Synovial membrane explants of these three patient groups were induced in vitro to undergo chondrogenesis by growth factors: bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-β1 (TGF-β1) alone, or a combination of these two. Quantitative evaluations of the newly formed cartilages were performed respecting their gene activities, as well as the histochemical, immunhistochemical, morphological and histomorphometrical characteristics. Formation of adult articular-like cartilage was induced by the BMP-2/TGF-β1 combination within all three groups, and was confirmed by adequate gene-expression levels of the anabolic chondrogenic markers; the levels of the catabolic markers remained low. Our data reveal that the chondrogenic potential of the normal human synovium remains uncompromised, both in FAI and OA. The potential of synovium-based clinical repair of joint cartilage may thus not be impaired by age-related joint pathologies. [ABSTRACT FROM AUTHOR]

Synovial membrane mesenchymal stem cells (SMSCs) often serve as in vitro model for bone disease, but the molecular mechanisms driving osteogenesis in SMSCs from different donor cells of various sources and breeds remain unclear. In this study, porcine SMSCs isolated from adipose synovium (FP) and fibrous synovium (FS) of Angeln Saddleback (AS) and German Landrace (DL) were used to discover the signaling network change after osteogenic induction. During osteogenic differentiation, mineral deposition was first observed at day 14 and further increased until day 21. Transcriptional changes between day 1 and day 21 were enriched in several signaling pathways, including Wnt, PI3K-Akt, and TGF-beta pathway. Certain pathways related to osteogenesis, including osteoblast differentiation, regulation of bone mineralization, and BMP signaling pathway, were enriched at late time points, as confirmed by the osteogenic markers ALPL, COL1A1, and NANOG. A fraction of differentially expressed genes (DEGs) were found between FP and FS, while DEGs between AS and DL increased during the differentiation phase until day 7 and then decreased from day 14 to day 21. These genes are involved in several important signaling pathways, including TGF-beta, Wnt, and lipid-related signaling pathways, suggesting that SMSCs from these two breeds have different osteogenic capabilities. [ABSTRACT FROM AUTHOR]

Image-guided synovial biopsy is generally a safe, well-tolerated procedure, with a high diagnostic yield. Percutaneous biopsy is indicated for synovial tumours visible on imaging studies where a definitive diagnosis is not possible on imaging grounds alone and/or when a definite diagnosis is necessary prior to initiating long-term treatment. Synovial biopsy for suspected synovial tumour differs from the technique used for joint aspiration, where the most convenient path between the skin and joint is usually chosen and, also, to a lesser degree, to that used for non-tumoural synovial biopsy. During synovial biopsy for tumour, the needle path should be aligned so that it passes along the length of the synovial tumour, including for suspected malignant tumours, the planned resection plane whenever possible. This review outlines the approach to image-guided biopsy of joint synovial tumours. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate whether synovium removal from the articular side of the quadriceps tendon around the superior pole of the patella after total knee arthroplasty (TKA) reduced the incidence of patellar crepitus (PC) or not.Methods: We retrospectively reviewed 134 consecutive patients who underwent primary posterior stabilized (PS)-TKA by one surgeon from 2010 to 2013. Sixty-seven patients performed without touching synovium at superior pole of patella and 67 patients performed with removing all synovium from superior pole of patella were compared; none had patellar resurfacing. Patients were followed up two and six weeks, three, six and 12 months and annually thereafter. The primary outcome was the incidence of PC, detected during follow-up, and was graded as absent (0), fine (1), or coarse (2).Results: At one year of follow-up, the synovial removal (SR) group had a significant lower rate of PC compared to the synovial preserved (SP) group: 15/67 (22%) vs 34/67 (51%), adjusted odds ratio = 0.29, 95% confidence interval (CI) = 0.14 to 0.64, P = 0.002. All PC in SR group were grade 1 while four knees in SP group were grade 2. Mean PC onset was eight months after surgery (range 1.5 to 12, P = 0.78) in both groups.Conclusion: Removal of the synovium from the articular side of the quadriceps tendon around the superior pole of patellar reduced the incidence of PC after primary PS-TKA without patellar resurfacing. This is a promising technique and might enlighten surgeons to reduce the noise and improve patient satisfaction after total knee replacement. [ABSTRACT FROM AUTHOR]

Objective: The excessive proliferation of fibroblast-like synoviocytes (FLSs) is a key inducement for the occurrence and development of rheumatoid arthritis (RA). Hypoxia inducible factor-α (HIF-α) accumulation is involved in the regulation of cell biological functions in the hypoxic microenvironment of synovium. This study aimed to investigate the roles of HIF-α and its level regulator prolyl hydroxylases (PHDs) in FLSs proliferation and to explore the regulatory effect of geniposide (GE). Materials and methods: Adjuvant arthritis rats and RA-FLSs cell line MH7A were taken as the research objects. MH7A cells were incubated in a hypoxic chamber with 2% O2 for hypoxia treatment. CCK-8, FACS, EdU and Western blot assays were performed to evaluate MH7A cells proliferation. Iron assay was conducted to determine intracellular Fe2+ level. Results: MH7A cells proliferation was significantly enhanced under hypoxia, accompanied by an increase of HIF-1α level. Decreased HIF-1α level by PX-478 inhibited MH7A cells proliferation. Furthermore, PHD2 was highly expressed in vivo and in vitro, and played a key role in modulation of HIF-1α protein level, which was confirmed by PHD2 inhibitor IOX4 and proteasome inhibitor MG132. GE treatment alleviated synovial hyperplasia in AA rats and inhibited MH7A cells proliferation with a reduction in HIF-1α level. Fe2+ acts as an enzymatic cofactor to control PHD2 activity. Iron assay showed that GE reversed the decline of Fe2+ level in MH7A cells under hypoxia. Conclusion: GE attenuates abnormal proliferation of RA-FLSs via inhibiting HIF-1α accumulation through enhancement of PHD2 activity. [ABSTRACT FROM AUTHOR]

Purpose: The current study aims to report the radiologic and clinical appearance of a rare anatomical variation of the knee medial synovial plica along with its response to conservative and surgical treatment. Case presentation: This report portrays a 29-year-old male patient with anteromedial gradual onset right knee pain, aggravated when descending stairs or prolonged sitting. Physical examination revealed medial parapatellar local tenderness, a palpable click in this area when the knee was extended, and hamstring tightness. Magnetic resonance imaging showed a duplicated medial plica, characterized by a high-intensity signal of the infrapatellar fat pad medial portion, after which a presumptive diagnosis of medial plica syndrome was proposed. After conservative treatment failure, the patient underwent standard knee arthroscopy that revealed a superior low profile and an inferior high profile medial plica, and hypertrophy of the medial portion of the infrapatellar fat pad. Both plicae and fat pad were resected with a mechanical shaver until no contact between the femoral trochlea and the fat pad was observed during full range of motion. At 4 weeks postoperatively, symptoms completely resolved, and the patient was allowed to return to full activity with no recurrences at 1 year follow-up. Conclusions: The current study presented a rare anatomical variation of the knee medial synovial plica that was symptomatic and recalcitrant to conservative treatment. This case report may be useful for radiologists and orthopaedic surgeons to differentiate this special plica type and consider its response to conservative and surgical treatment during patient management. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory illness caused by an autoimmune disorder of synovial membrane resulting in synovial membrane dysfunction. The available treatment particularly focuses on inhibiting macrophage proliferation and reducing the generation of pro-inflammatory cytokines. However, therapeutic success of current treatment options at targeted site is limited; therefore, development of promising therapeutic strategy is the need of time that may provide better targeted delivery of drug with added safety. In development of precision medicine to manage RA, nanotechnology is a viable option to be considered. Recent research using nanoparticles for the treatment of RA, particularly polymeric nanoparticles, has been discussed in this article. Using polymeric nanoparticles as a therapeutic method has shown considerable promise of enhancing treatment success over standard medications used in routine. It is exclusively evident that the viability of using nanoparticles is mainly owed due to their biocompatibility, chemical stability, controlled drug release, and selective drug delivery to inflamed tissues in RA model animals. The current analysis focuses on the critical design characteristics of RA-targeted nanotechnology-based strategies in quest of better therapeutic strategies for RA, and to identify leading polymer as the most effective medications in RA therapy. [ABSTRACT FROM AUTHOR]

To directly compare and describe the differences between juvenile idiopathic arthritis (JIA) patients and pediatric controls regarding features of the synovial and tenosynovial membrane on contrast-enhanced magnetic resonance imaging (MRI) of the wrist. T1-weighted contrast-enhanced MRI scans of 25 JIA patients with clinically active wrist arthritis and 25 children without a history of joint complaints nor any clinical signs of joint inflammation were evaluated by two readers blinded to clinical data. The synovium was scored at five anatomical sites based on thickening of the synovium (0–3 scale) and synovial enhancement (0–2 scale). Thickening and/or enhancement of the tenosynovium was scored at four anatomical sites using a 0–3 scale. Significantly higher scores for synovial thickening (median 4 vs. 1, p < 0.001) and synovial enhancement (median 4 vs. 1, p < 0.001) are found in the wrist of JIA patients as compared to controls. JIA patients experienced the highest synovial scores at the mid-/inter-carpal, 2nd –5th carpometacarpal, and radiocarpal joints. No significant difference in tenosynovial scores is found between both groups (median 0 vs. 0, p = 0.220). This study highlights the higher synovial thickening/enhancement scores on contrast-enhanced MRI of the wrist in JIA patients compared to pediatric controls. Tenosynovial thickening and/or enhancement was rarely present in both groups. In JIA patients, synovial thickening and enhancement were particularly present at three anatomical sites. These results substantially support rheumatologists and radiologists when navigating through MRI of the wrist in search for JIA disease activity. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease that gradually affects the synovial membrane and joints. Many intrinsic and/or extrinsic factors are crucial in making RA pathology challenging throughout the disease. Substantial enzymatic or non-enzymatic modification of proteins driving inflammation has gained a lot of interest in recent years. Endogenously modified glycated protein influences disease development linked with AGEs/non-AGEs and is reported as a disease marker. In this review, we summarized current knowledge of the differential abundance of glycated proteins by compiling and analyzing a variety of AGE and non-AGE ligands that bind with RAGE to activate multi-faceted inflammatory and oxidative stress pathways that are pathobiologically associated with RA-fibroblast-like synoviocytes (RA-FLS). It is critical to comprehend the connection between oxidative stress and inflammation generation, mediated by glycated protein, which may bind to the receptor RAGE, activate downstream pathways, and impart immunogenicity in RA. It is worth noting that AGEs and non-AGEs ligands play a variety of functions, and their functionality is likely to be more reliant on pathogenic states and severity that may serve as biomarkers for RA. Screening and monitoring of these differentially glycated proteins, as well as their stability in circulation, in combination with established pre-clinical characteristics, may aid or predict the onset of RA. [ABSTRACT FROM AUTHOR]

Introduction: Arthrofibrosis is a relatively frequent complication after total knee arthroplasty. Although stiffness after total hip arthroplasty (THA), because of formation of heterotopic ossification or other causes, is not uncommon, to the authors' best knowledge, arthrofibrosis after THA has not been described. The aim of this study is to describe the arthrofibrosis of the hip after primary THA using an established clinical and histological classification of arthrofibrosis. Materials and methods: We retrospectively examined all patients who were histologically confirmed to have arthrofibrosis after primary THA during revision surgery by examination of tissue samples in our clinic. Arthrofibrosis was diagnosed according to the histopathological SLIM-consensus classification, which defines seven different SLIM types of the periimplant synovial membrane. The SLIM type V determines the diagnosis of endoprosthesis-associated arthrofibrosis. Results: The study population consists of 66 patients who were revised due to arthrofibrosis after primary THA. All patients had a limitation in range of motion prior to revision with a mean flexion of 90° (range from 40 to 125), mean internal rotation of 10° (range from 0 to 40) and mean external rotation of 20° (range from 0 to 50). All patients had histological SLIM type V arthrofibrosis, corresponding to endoprosthesis-associated arthrofibrosis. Histological examination revealed that seven patients (10.6%) had particle-induced and 59 patients (89.4%) had non-particle-induced arthrofibrosis. Conclusion: This is the first description of endoprosthetic-associated arthrofibrosis after primary THA on the basis of a well-established histological classification. Our study results could enable new therapeutic and diagnostic opportunities in patients with such an arthrofibrosis. Surgeons should keep arthrofibrosis as a possible cause for stiffness and pain after primary THA in mind. Level of evidence: Diagnostic study, Level of Evidence IV. [ABSTRACT FROM AUTHOR]

Introduction: Frozen shoulder (adhesive capsulitis) is a common painful and functionally-limiting disease affecting around 2% of the population. So far, therapeutic options are limited and often unsatisfactory. Platelet-rich plasma (PRP) has been used as a treatment option in other orthopedic diseases since it contains growth factors that stimulate tissue repair. So far, the effect of PRP on frozen shoulder lacks evidence. We hypothesized that PRP may be valuable in the prophylaxis and treatment of secondary frozen shoulder due to capsular remodeling. Materials and methods: An experimental study of an in vivo frozen shoulder model was conducted. Twenty Sprague–Dawley rats underwent surgery in which the body of the scapula was connected to the humerus with a high-strength suture. Two groups of 8 weeks survival time were allocated; a treatment group with one intraoperative injection of PRP into the glenohumeral joint (n = 10) and a control group without PRP (n = 10). The primary outcome was the structural change in the posterior synovial membrane of the posterior and inferior part of the glenohumeral joint using a semi-quantitative grading from 0 (lowest) to 3 (highest). Results: The posterior synovial membrane structural changes were significantly lower in the PRP group (median = 1 [interquartile range (IQR) = 0–1]) compared to controls (median = 2 [IQR = 1–3]) (p = 0.028). There were no differences for the remaining synovial membrane changes and fibrous capsule responses between groups. Conclusions: In this in vivo shoulder contracture model, PRP injections seem to reduce the histological severity grade of some parts (i.e., posterior synovial membrane changes) of the secondary frozen shoulder without causing any side effects. It may be considered to investigate this effect further in future studies as a potential prophylaxis of secondary frozen shoulder (e.g., in operated or immobilized shoulders) or as a treatment option for patients with frozen shoulder in the early stage. [ABSTRACT FROM AUTHOR]

The inflamed rheumatic joint is a highly heterogeneous and complex tissue with dynamic recruitment and expansion of multiple cell types that interact in multifaceted ways within a localized area. Rheumatoid arthritis synovium has primarily been studied either by immunostaining or by molecular profiling after tissue homogenization. Here, we use Spatial Transcriptomics, where tissue-resident RNA is spatially labeled in situ with barcodes in a transcriptome-wide fashion, to study local tissue interactions at the site of chronic synovial inflammation. We report comprehensive spatial RNA-Seq data coupled to cell type-specific localization patterns at and around organized structures of infiltrating leukocyte cells in the synovium. Combining morphological features and high-throughput spatially resolved transcriptomics may be able to provide higher statistical power and more insights into monitoring disease severity and treatment-specific responses in seropositive and seronegative rheumatoid arthritis. Sanja Vickovic et al. use spatial transcriptomics to probe the local synovial tissue interactions in rheumatoid arthritis (RA) patients. Their results provide a valuable resource to understand the spatial organisation of cell populations in the synovium in the context of RA-associated inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Radiosynoviorthesis (RSO) using the intraarticular application of beta-particle emitting radiocolloids has for decades been used for the local treatment of inflammatory joint diseases. The injected radiopharmaceuticals are phagocytized by the superficial macrophages of the synovial membrane, resulting in sclerosis and fibrosis of the formerly inflamed tissue, finally leading to reduced joint effusion and alleviation of joint pain. Methods: The European Association of Nuclear Medicine (EANM) has written and approved these guidelines in tight collaboration with an international team of clinical experts, including rheumatologists. Besides clinical and procedural aspects, different national legislative issues, dosimetric considerations, possible complications, and side effects are addressed. Conclusion: These guidelines will assist nuclear medicine physicians in performing radiosynoviorthesis. Since there are differences regarding the radiopharmaceuticals approved for RSO and the official indications between several European countries, this guideline can only give a framework that must be adopted individually. [ABSTRACT FROM AUTHOR]

The objective of this work was to assess the consequences of repeated intra-articular injection of monosodium urate (MSU) crystals with inflammasome priming by lipopolysaccharide (LPS) in order to simulate recurrent bouts of gout in rats. Translational imaging was applied to simultaneously detect and quantify injury in different areas of the knee joint. MSU/LPS induced joint swelling, synovial membrane thickening, fibrosis of the infrapatellar fat pad, tidemark breaching, and cartilage invasion by inflammatory cells. A higher sensitivity to mechanical stimulus was detected in paws of limbs receiving MSU/LPS compared to saline-injected limbs. In MSU/LPS-challenged joints, magnetic resonance imaging (MRI) revealed increased synovial fluid volume in the posterior region of the joint, alterations in the infrapatellar fat pad reflecting a progressive decrease of fat volume and fibrosis formation, and a significant increase in the relaxation time T2 in femoral cartilage, consistent with a reduction of proteoglycan content. MRI also showed cyst formation in the tibia, femur remodeling, and T2 reductions in extensor muscles consistent with fibrosis development. Repeated intra-articular MSU/LPS injections in the rat knee joint induced pathology in multiple tissues and may be a useful means to investigate the relationship between urate crystal deposition and the development of degenerative joint disease. [ABSTRACT FROM AUTHOR]

Synovium-derived mesenchymal stromal cell (Sy-MSC) is a newer member of the mesenchymal stromal cell families. The first successful demonstration of the mesenchymal stromal cell from the human synovial membrane was done in 2001 and since then its potential role for musculoskeletal regeneration has been keenly documented. The regenerative effects of Sy-MSCs are through paracrine signaling, direct cell–cell interactions, and extracellular vehicles. Sy-MSCs possess superior chondrogenicity than other sources of mesenchymal stromal cells. This article aims to outline the advancement of synovium-derived mesenchymal stromal cells along with a specific insight into the application for managing osteoarthritis knee. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLS) play an important pathological role in persistent inflammatory joint diseases such as rheumatoid arthritis (RA). These cells have primarily been characterized in the RA synovial membrane. Here we aim to phenotypically and functionally characterize cultured synovial fluid-derived FLS (sfRA-FLS). Paired peripheral blood mononuclear cells (PBMC) and sfRA-FLS from patients with RA were obtained and monocultures of sfRA-FLS and autologous co-cultures of sfRA-FLS and PBMC were established. The in situ activated sfRA-FLS were CD34-, CD45-, Podoplanin+, Thymocyte differentiation antigen-1+. SfRA-FLS expressed uniform levels of NFкB-related pathway proteins and secreted several pro-inflammatory cytokines dominated by IL-6 and MCP-1. In a co-culture model with autologous PBMC, the ICAM-1 and HLA-DR expression on sfRA-FLS and secretion of IL-1β, IL-6, and MCP-1 increased. In vivo, human sfRA-FLS were cartilage invasive both at ipsilateral and contralateral implantation site. We conclude that, sfRA-FLS closely resemble the pathological sublining layer FLS subset in terms of surface protein expression, cytokine production and leukocyte cross-talk potential. Further, sfRA-FLS are comparable to tissue-derived FLS in their capabilities to invade cartilage at implantation sites but also spread tissue destruction to a distant site. Collectively, sfRA-FLS can serve as a an easy-to-obtain source of pathological sublining FLS in RA. [ABSTRACT FROM AUTHOR]

Data demonstrating that antibiotics administered intraoperatively in patients with surgical revision for periprosthetic joint infection achieve concentrations exceeding minimal inhibitory concentrations of the identified bacteria at the surgical site when the new implant is inserted are lacking. We prospectively included patients with periprosthetic joint infection operated with one- or two-stage replacement during which cefepime (2g)-daptomycin (10mg/kg) combination was administered intravenously as intraoperative empirical antibiotic treatment. Three biopsies (two bones and one synovial membrane) were taken from each patient just before the insertion of the new implant. Eighteen adults of median age 68 years were included. Knee was involved in 10 patients (55.6%) and surgery consisted in one-/two-stage replacement in 11/7 patients. A tourniquet was used during the intervention in the 10 patients with knee prosthesis. Among 54 tissue samples, cefepime and daptomycin were detected respectively in 35 (64.8%) and 21 (38.9%) cases (P=0.01). A total of 17 bacteria dominated by staphylococci (n=14) were identified in 10 patients; tissue inhibitory quotient calculated in 51 samples was >1 in 22 cases (43.1%) for cefepime and in 16 cases (31.4%) for daptomycin. The proportion of tissue samples with detectable antibiotic was significantly higher in hip versus knee prosthesis (P=0.03). The present study suggests that intraoperative empirical administration of cefepime-daptomycin combination during septic prosthetic joint replacement results in a high proportion of tissue samples in which at least one of the two antibiotics was not detected or at a low concentration despite satisfactory concomitant blood serum concentrations. [ABSTRACT FROM AUTHOR]

Background: Drugs that can induce mesenchymal stem cell (MSC) mobilization from synovium into synovial fluid will enable regenerative medicine in joints without use of exogenous MSCs. An in vitro synovial MSC migration model had previously been developed for screening but had problems in practical application. We herein developed a novel in vitro model, explored cytokines for synovial MSC mobilization with this model, and verified whether MSCs in synovial fluid increase following intra-articular injection of the cytokine. Methods: Human synovial MSCs embedded in a mixture of Matrigel and type 1 collagen hydrogel were placed on a culture insert and then put in medium containing migration factor. Of the six cytokines, we identified the one that mobilizes the highest number of MSCs. PDGF-BB or PBS was injected into rat knees, and 48 h later, synovial fluid was collected and cultured. The cells were examined for MSC properties. Results: PDGF-BB was the most effective for synovial MSC mobilization among six cytokines. The effect of PDGF-BB was inhibited by a PRGFR inhibitor. Injection of PDGF-BB into rat knees increased colony-forming cells in the synovial fluid. These cells had surface epitopes and multipotency comparable to MSCs and a higher capacity for proliferation, colony formation, and chondrogenesis. Conclusions: This novel in vitro model recapitulated the migration of MSCs from synovium into synovial fluid. Our exploration of cytokines revealed that PDGF-BB strongly induced in vitro synovial MSC migration, while intra-articular injection of PDGF-BB increased in vivo MSC numbers in synovial fluid in rats. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a whole-joint disease characterized by subchondral bone perfusion abnormalities and neovascular invasion into the synovium and articular cartilage. In addition to local vascular disturbance, mounting evidence suggests a pivotal role for systemic vascular pathology in the aetiology of OA. This Review outlines the current understanding of the close relationship between high blood pressure (hypertension) and OA at the crossroads of epidemiology and molecular biology. As one of the most common comorbidities in patients with OA, hypertension can disrupt joint homeostasis both biophysically and biochemically. High blood pressure can increase intraosseous pressure and cause hypoxia, which in turn triggers subchondral bone and osteochondral junction remodelling. Furthermore, systemic activation of the renin-angiotensin and endothelin systems can affect the Wnt-β-catenin signalling pathway locally to govern joint disease. The intimate relationship between hypertension and OA indicates that endothelium-targeted strategies, including re-purposed FDA-approved antihypertensive drugs, could be useful in the treatment of OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic, debilitating disease affecting millions of people worldwide. Management of OA involves pharmacological and non-pharmacological approaches. Conventional pharmacological treatments have limited efficacy and are associated with a number of side-effects, restricting the number of patients who can use them. New pharmacological therapies for managing OA are required and a number have been developed targeting different tissues in OA: bone and cartilage, synovium and nerves. However, there has been overall limited success. Disease-modifying osteoarthritis drugs (DMOADs) are a putative class of therapies aimed at improving OA structural pathologies and consequent symptoms. Recent DMOAD studies have demonstrated some promising therapies but also provided new considerations for future trials. [ABSTRACT FROM AUTHOR]

New research has identified apolipoprotein E expressed by fibroblasts and macrophages in the infrapatellar fat pad and synovium as a pathogenetic mediator and potential therapeutic target in knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Spondyloarthritis (SpA) is a group of chronic, immune-mediated, inflammatory diseases affecting the bone, synovium, and enthesis. Microbiome, the community of microorganisms that has co-evolved with human hosts, plays a pivotal role in human health and disease. This invisible "essential organ" supplies the host with a myriad of chemicals and molecules. In turn, microbial metabolites can serve as messengers for microbes to communicate with each other and in the cross-talk with host cells. Gut dysbiosis in SpA is associated with altered microbial metabolites, and an accumulated body of research has contributed to the understanding that changes in intestinal microbiota can modulate disease pathogenesis. We review the novel findings from human and animal studies to provide an overview of the contribution of individual microbial metabolites and antigens to SpA. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLSs) are important non-immune cells located mostly in the inner layer of the synovium. Indeed, these cells are specialized mesenchymal cells, implicated in collagen homeostasis of the articular joint and provide extracellular matrix (ECM) materials for cartilage and contribute to joint destruction via multiple mechanisms. RA FLS interactions with immune and non-immune cells lead to the development and organization of tertiary structures such as ectopic lymphoid-like structures (ELSs), tertiary lymphoid organs (TLOs), and secretion of proinflammatory cytokines. The interaction of RA FLS cells with immune and non-immune cells leads to stimulation and activation of effector immune cells. Pathological role of RA FLS cells has been reported for many years, while molecular and cellular mechanisms are not completely understood yet. In this review, we tried to summarize the latest findings about the role of FLS cells in ELS formation, joint destruction, interactions with immune and non-immune cells, as well as potential therapeutic options in rheumatoid arthritis (RA) treatment. Our study revealed data about interactions between RA FLS and immune/non-immune cells as well as the role of RA FLS cells in joint damage, ELS formation, and neoangiogenesis, which provide useful information for developing new approaches for RA treatment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis synovium contains phenotypically and functionally heterogeneous fibroblast-like synoviocytes. Cutting-edge analyses have now defined at least four distinct states of these cells related to their location in the synovium, epigenetic imprinting and the influence of microenvironment mediators. [ABSTRACT FROM AUTHOR]

A tenosynovial giant cell tumor is a benign proliferative disease, mostly arising from the synovial membrane of tendon sheaths, bursae, and joints. Axial skeleton involvement is very rare, but it is often found in the cervical spine. Spinal tenosynovial giant cell tumors often arise at the facet joints; a completely extra-articular spinal tenosynovial giant cell tumor is rare. We report an extremely rare case of tenosynovial giant cell tumor in the upper cervical spine that extended from the posterior atlanto-occipital membrane rather than the facet joint. Herein, the clinical and radiological findings will be reviewed to better our understanding of the characteristics of spinal tenosynovial giant cell tumors, and to help improve their diagnosis despite their non-typical locations of origin. [ABSTRACT FROM AUTHOR]

The anti-inflammatory effect of the ester derivative of indomethacin (IML) in doses of 6.25, 12.5, and 25 mg/kg was studied in rats with modeled rheumatoid arthritis (adjuvant arthritis) and compared to the effects of the reference drug indomethacin in a dose of 1 mg/kg. IML in doses of 12.5 and 25 mg/kg reduced joint inflammation and promoted recovery of the microstructure of the synovial membrane and articular cartilage better than indomethacin. IML produced no ulcerogenic effect, while indomethacin concentration in the stomach wall after administration of IML was 1.8-3.4 times lower than after administration of the reference drug (p<0.05). [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF); is an autosomal recessively inherited autoinflammatory disease caused by the mutations in the Mediterranean Fever (MEFV) gene. Recent studies have shown that epigenetic control mechanisms, particularly non-coding RNAs, may play a role in the pathogenesis of autoinflammation. microRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating host gene expression at the post-transcriptional level. The phenotypic heterogeneity of FMF disease suggests that FMF may not be a monogenic disease, suggesting that epigenetic factors may affect phenotypic presentation. Here we examined the potential anti-inflammatory effect of miR-197-3p, which is a differentially expressed miRNA in FMF patients, by using inflammation related functional assays. We monitored gene expression levels of important cytokines, as well as performed functional studies on IL-1β secretion, caspase-1 activation, apoptosis assay, and cell migration assay. These experiments were used to evaluate the different stages of inflammation following pre-miR-197 transfection. Anti-miR-197 transfections were performed to test the opposite effect. 3′UTR luciferase activity assay was used for target gene studies. Our results obtained by inflammation-related functional assays demonstrated an anti-inflammatory effect of miR-197-3p in different cell types (synovial fibroblasts, monocytes, macrophages). 3′UTR luciferase activity assay showed that miR-197-3p directly binds to the interleukin-1beta (IL-1β) receptor, type I (IL1R1) gene, which is one of the key molecules of the inflammatory pathways. This study may contribute to understand the role of miR-197-3p in autoinflammation process. Defining the critical miRNAs may guide the medical community in a more personalized medicine in autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Objectives: The synovial membrane and fluid are involved in the pathogenesis of temporomandibular joint (TMJ) disorders. This study aims to assess the relationship between matrix metalloproteinase-2 (MMP-2), chemerin and prostaglandin (PGE2) levels in the synovial fluid (SF) and saliva of patients with TMJ disorder regarding their role in inflammation and the value of being a candidate for predictive biomarkers in the disease. Also, it is aimed to find out whether chemerin's main function triggers the formation inflammatory cytokine markers in the associated area. Materials and methods: Thirty-two samples of SF and saliva were obtained from patients with disc displacement without reduction with limited opening (DDWORwLO). Mann-Whitney-U test was used for the comparisons of the biomarker levels in SF and saliva. The correlation between chemerin and BMI (Body Mass Index) is analyzed by non-parametric Spearman's rho correlation coefficient. Results: For all of the three biomarkers, statistically significant differences were found between SF and saliva. An unexpectedly high level expression of chemerin was observed in SF. A statistically significant, positive correlation was observed between PGE2 -MMP-2, and chemerin-PGE2 in saliva, chemerin and MMP-2 in SF, respectively (p = 0.031, r = 0.382 / p = 0.039, r = 0.366 / p = 0.032, r = 0.379). A positive correlation was determined between saliva and SF levels of PGE2 (p = 0.016, r = 0.421). Conclusions: Chemerin, MMP-2, and PGE2 can play a role as an inflammatory factor for the development of TMJ disorder. Clinical relevance: The search for molecular markers in TMJ and the inhibition of the associated molecular signaling mechanism is important to reduce joint inflammation and cartilage degradation. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a long-term inflammatory disease derived from an autoimmune disorder of the synovial membrane. Current therapeutic strategies for RA mainly aim to hamper the macrophages' proliferation and reduce the production of pro-inflammatory cytokines. Therefore, the accumulation of therapeutic agents targeted at the inflammatory site should be a crucial therapeutic strategy. Nowadays, the nanocarrier system incorporated with stimuli-responsive property is being intensively studied, showing the potentially tremendous value of specific therapy. Stimuli-responsive (i.e., pH, temperature, light, redox, and enzyme) polymeric nanomaterials, as an important component of nanoparticulate carriers, have been intensively developed for various diseases treatment. A survey of the literature suggests that the use of targeted nanocarriers to deliver therapeutic agents (nanotherapeutics) in the treatment of inflammatory arthritis remains largely unexplored. The lack of suitable stimuli-sensitive polymeric nanomaterials is one of the limitations. Herein, we provide an overview of drug delivery systems prepared from commonly used stimuli-sensitive polymeric nanomaterials and some inorganic agents that have potential in the treatment of RA. The current situation and challenges are also discussed to stimulate a novel thinking about the development of nanomedicine. [ABSTRACT FROM AUTHOR]

Aims and Objectives: The purpose of this study was to compare the potential effects of pedunculated and free synovial grafts in the repair of full-thickness articular cartilage defects on an animal model with histological and immunohistochemical analysis. Materials and Methods: A comparative study in an animal model was performed with 24 rabbits, divided into two groups. Full-thickness cartilage defects were created bilaterally on the knees of all rabbits. Pedunculated and free synovial grafts were applied to the right knees of Group 1 and Group 2, respectively. Left knees were left as the control group. Six rabbits from each group were randomly selected for euthanasia 4 and 8 weeks postoperatively. All samples were examined histologically with a cartilage scoring system. For immunohistochemical analysis, the degree of collagen 2 staining was determined using a staging system. All data were statistically compared between the study groups with Student's t-test or Mann–Whitney U-test. The correlations between categorical variables were analyzed with Fisher's exact test and Chi-square test. Results: In Group 1, the mean defect size had significantly decreased at 8 weeks postsurgery. It was also significantly smaller than that of Group 2. Both pedunculated and free synovial grafts had significantly better histological and immunohistochemical outcomes compared with the controls. Contrastingly, the results of comparison between the study groups (Group 1 vs. 2) at the 4th and 8th week were not statistically significant with regard to histological scores and immunohistochemical staining. Conclusion: Synovial tissue, whether pedunculated or free, provided much better cartilage recovery compared with the control. It can be used as a mesenchymal stem cell (MSC) source, and synovium-derived MSCs have the chondrogenic potential for the in vivo treatment of full-thickness cartilage defects. [ABSTRACT FROM AUTHOR]

Background: Knowledge of the synovial and tenosynovial appearance of the clinically non-arthritic symptomatic juvenile wrist using contrast-enhanced magnetic resonance imaging (MRI) is sparse. Objectives: To analyze contrast-enhanced MRI findings of the clinically non-inflamed symptomatic pediatric wrist, focusing on the enhancing synovial and tenosynovial membrane. To evaluate the coexistent presence of (teno)synovial enhancement, joint fluid, bony depressions and medullary changes suggestive of bone marrow edema. Materials and methods: We included 20 children (15 girls; age range: 7.5–17.6 years) who underwent contrast-enhanced MRI of the wrist, based on initial clinical indication, and eventually turned out to be unaffected by arthritic or orthopedic disorders. Various imaging characteristics of the synovium, tenosynovium, joint fluid, bone tissue and bone marrow were evaluated using existing MRI scoring systems. Results: In 3/20 (15%) children, mild or moderate-severe synovial enhancement was observed and 2/20 (10%) children showed mild tenosynovial enhancement/thickening. Joint fluid (11/20 children; 55%), bony depressions (20/20 children; 100%) and medullary changes suggestive of bone marrow edema (6/20; 30%) were found in a substantial percentage of children. The most frequently observed combination of coexisting imaging characteristics was bony depressions with ≥2 mm joint fluid, which was found in 7/20 (35%) children. Simultaneous presence of synovial and tenosynovial enhancement/thickening, bony depressions and medullary changes suggestive of bone marrow edema was observed in one child. Conclusion: Several juvenile idiopathic arthritis-relevant MRI characteristics can be observed in the clinically non-inflamed symptomatic pediatric wrist. [ABSTRACT FROM AUTHOR]

The current study was aimed to identify diagnostic gene signature for osteoarthritis (OA). The differentially expressed genes (DEGs) in synovial membrane samples and blood samples were respectively identified from the GEO dataset. The intersection DEGs between synovial membrane and blood were further screened out, followed by the functional annotation of these common DEGs. The optimal intersection gene biomarkers for OA diagnostics were determined. The GSE51588 dataset of articular cartilage was used for expression validation and further diagnostic analysis validation of identified gene biomarkers for OA diagnostics. There were 379 intersection DEGs were obtained between the synovial membrane and blood samples of OA. 22 DEGs had a diagnostic value for OA. After further screening, a total of 9 DEGs including TLR7, RTP4, CRIP1, ZNF688, TOP1, EIF1AY, RAB2A, ZNF281 and UIMC1 were identified for OA diagnostic. The identified DEGs could be considered as potential diagnostic biomarkers for OA. [ABSTRACT FROM AUTHOR]

There have been many attempts to visualize the inflamed joints using multiphoton microscopy. However, due to the hypervascular and multilayered structure of the inflamed synovium, intravital imaging of the deep synovial tissue has been difficult. Here, we established original intravital imaging systems to visualize synovial tissue and pathological osteoclasts at the pannus–bone interface using multiphoton microscopy. Combined with fluorescence-labeling of CTLA-4 Ig, a biological agent used for the treatment of rheumatoid arthritis, we identified that CTLA-4 Ig was distributed predominantly within the inflamed synovium and bound to CX3CR1+ macrophages and CD140a+ fibroblasts 6 h after injection, but not to mature osteoclasts. Intravital imaging of blood and lymphatic vessels in the inflamed synovium further showed that extravasated CTLA-4 Ig was immediately drained through lymphatic vessels under acute arthritic conditions, but the drainage activity was retarded under chronic conditions. These results indicate that this intravital synovial imaging system can serve as a platform for exploring the dynamics of immune cells, osteoclasts, and biological agents within the synovial microenvironment in vivo. [ABSTRACT FROM AUTHOR]