Review

Authors: Elsa Sanchez-Lopez, Roxana Coras, Alyssa Torres...

Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with radiographic and pain progression. Several OA risk factors, including ageing, obesity, trauma and mechanical loading, play a role in OA pathogenesis, likely by modifying synovial biology. In addition, other factors, such as mitochondrial dysfunction, damage-associated molecular patterns, cytokines, metabolites and crystals in the synovium, activate synovial cells and mediate synovial inflammation. An understanding of the activated pathways that are involved in OA-related synovial inflammation could form the basis for the stratification of patients and the development of novel therapeutics. This Review focuses on the biology of the OA synovium, how the cells residing in or recruited to the synovium interact with each other, how they become activated, how they contribute to OA progression and their interplay with other joint structures.

Topics: Cytokines; Humans; Inflammation; Osteoarthritis; Synovial Membrane; Synoviocytes

PubMed: 35165404
DOI: 10.1038/s41584-022-00749-9

Authors: Jie Yang, Shanshan Li, Zhenyan Li...

The interplay between immune cells/macrophages and fibroblast-like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single-cell RNA sequencing (scRNA-seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients' synovial macrophage infiltration and polarization. In addition, the yes-associated protein 1 (YAP1)/thioredoxin-interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)-dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) which may subsequently fine-tune the infiltration of M1-polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane-camouflaged Verteporfin (Vt)-loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1-polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Topics: Humans; Mice; Animals; Synoviocytes; Osteoarthritis; Macrophages; Transcription Factors; Adaptor Proteins, Signal Transducing; Diabetes Mellitus; Fibroblasts; Glycolysis

PubMed: 38044289
DOI: 10.1002/advs.202304617

Authors: Bin Liu, Yansi Xian, Xiang Chen...

The severity of osteoarthritis (OA) and cartilage degeneration is highly associated with synovial inflammation. Although recent investigations have revealed a dysregulated crosstalk between fibroblast-like synoviocytes (FLSs) and macrophages in the pathogenesis of synovitis, limited knowledge is available regarding the involvement of exosomes. Here, increased exosome secretion is observed in FLSs from OA patients. Notably, internalization of inflammatory FLS-derived exosomes (inf-exo) can enhance the M1 polarization of macrophages, which further induces an OA-like phenotype in co-cultured chondrocytes. Intra-articular injection of inf-exo induces synovitis and exacerbates OA progression in murine models. In addition, it is demonstrated that inf-exo stimulation triggers the activation of glycolysis. Inhibition of glycolysis using 2-DG successfully attenuates excessive M1 polarization triggered by inf-exo. Mechanistically, HIF1A is identified as the determinant transcription factor, inhibition of which, both pharmacologically or genetically, relieves macrophage inflammation triggered by inf-exo-induced hyperglycolysis. Furthermore, in vivo administration of an HIF1A inhibitor alleviates experimental OA. The results provide novel insights into the involvement of FLS-derived exosomes in OA pathogenesis, suggesting that inf-exo-induced macrophage dysfunction represents an attractive target for OA therapy.

Topics: Humans; Mice; Animals; Synoviocytes; Exosomes; Cells, Cultured; Osteoarthritis; Inflammation; Synovitis; Fibroblasts; Macrophages; Glycolysis

PubMed: 38342630
DOI: 10.1002/advs.202307338

Authors: Ching-Heng Chou, Vaibhav Jain, Jason Gibson...

We elucidated the molecular cross-talk between cartilage and synovium in osteoarthritis, the most widespread arthritis in the world, using the powerful tool of single-cell RNA-sequencing. Multiple cell types were identified based on profiling of 10,640 synoviocytes and 26,192 chondrocytes: 12 distinct synovial cell types and 7 distinct articular chondrocyte phenotypes from matched tissues. Intact cartilage was enriched for homeostatic and hypertrophic chondrocytes, while damaged cartilage was enriched for prefibro- and fibro-, regulatory, reparative and prehypertrophic chondrocytes. A total of 61 cytokines and growth factors were predicted to regulate the 7 chondrocyte cell phenotypes. Based on production by > 1% of cells, 55% of the cytokines were produced by synovial cells (39% exclusive to synoviocytes and not expressed by chondrocytes) and their presence in osteoarthritic synovial fluid confirmed. The synoviocytes producing IL-1beta (a classic pathogenic cytokine in osteoarthritis), mainly inflammatory macrophages and dendritic cells, were characterized by co-expression of surface proteins corresponding to HLA-DQA1, HLA-DQA2, OLR1 or TLR2. Strategies to deplete these pathogenic intra-articular cell subpopulations could be a therapeutic option for human osteoarthritis.

Topics: Aged; Biomarkers; Cartilage, Articular; Case-Control Studies; Cells, Cultured; Female; Humans; Male; Osteoarthritis; RNA-Seq; Synoviocytes

PubMed: 32616761
DOI: 10.1038/s41598-020-67730-y

Review

Authors: Vladislav Tsaltskan, Gary S Firestein

Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the synovial fluid and articular cartilage. In rheumatoid arthritis (RA), however, fibroblasts become a key driver of synovial inflammation and joint damage. Because of this, there has been recent interest in FLS as a therapeutic target in RA to avoid side effects such as systemic immune suppression associated with many existing RA treatments. In this review, we describe how approved treatments for RA affect FLS signaling and function and discuss the effects of investigational FLS-targeted drugs for RA.

Topics: Humans; Synoviocytes; Synovial Membrane; Arthritis, Rheumatoid; Fibroblasts; Signal Transduction

PubMed: 36228471
DOI: 10.1016/j.coph.2022.102304

Authors: Helal Endisha, Poulami Datta, Anirudh Sharma...

OBJECTIVE

MicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of patients with late-stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remain to be fully elucidated. This study was undertaken to examine the role of miR-34a-5p in OA pathogenesis.

METHODS

Expression of miR-34a-5p was determined in joint tissues and human plasma (n = 71). Experiments using miR-34a-5p mimic or antisense oligonucleotide (ASO) treatment were performed in human OA chondrocytes, fibroblast-like synoviocytes (FLS) (n = 7-9), and mouse OA models, including destabilization of the medial meniscus (DMM; n = 22) and the accelerated, more severe model of mice fed a high-fat diet and subjected to DMM (n = 11). Wild-type (WT) mice (n = 9) and miR-34a-knockout (KO) mice (n = 11) were subjected to DMM. Results were expressed as the mean ± SEM and analyzed by t-test or analysis of variance, with appropriate post hoc tests. P values less than 0.05 were considered significant. RNA sequencing was performed on WT and KO mouse chondrocytes.

RESULTS

Expression of miR-34a-5p was significantly increased in the plasma, cartilage, and synovium of patients with late-stage OA and in the cartilage and synovium of mice subjected to DMM. Plasma miR-34a-5p expression was significantly increased in obese patients with late-stage OA, and in the plasma and knee joints of mice fed a high-fat diet. In human OA chondrocytes and FLS, miR-34a-5p mimic increased key OA pathology markers, while miR-34a-5p ASO improved cellular gene expression. Intraarticular miR-34a-5p mimic injection induced an OA-like phenotype. Conversely, miR-34a-5p ASO injection imparted cartilage-protective effects in the DMM and high-fat diet/DMM models. The miR-34a-KO mice exhibited protection against DMM-induced cartilage damage. RNA sequencing of WT and KO chondrocytes revealed a putative miR-34a-5p signaling network.

CONCLUSION

Our findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.

Topics: Adult; Aged; Animals; Cartilage, Articular; Chondrocytes; Diet, High-Fat; Disease Models, Animal; Female; Humans; Male; Menisci, Tibial; Mice; Mice, Knockout; MicroRNAs; Middle Aged; Oligonucleotides, Antisense; Osteoarthritis; Osteoarthritis, Knee; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Synoviocytes

PubMed: 33034147
DOI: 10.1002/art.41552

Authors: Stephan Culemann, Anika Grüneboom, José Ángel Nicolás-Ávila...

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CXCR1 tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CXCR1 mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CXCR1 lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.

Topics: Animals; Arthritis; CX3C Chemokine Receptor 1; Cell Tracking; Female; Gene Expression Profiling; Humans; Inflammation; Joints; Macrophages; Male; Mice; Mice, Inbred C57BL; Principal Component Analysis; RNA-Seq; Single-Cell Analysis; Synovial Membrane; Synoviocytes; Tight Junctions; Transcriptome

PubMed: 31391580
DOI: 10.1038/s41586-019-1471-1

Review

Authors: Jianan Zhao, Shicheng Guo, Steven J Schrodi...

Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients' physical and mental health, leading to chronic synovitis and destruction of bone joints. Although various available clinical treatment options exist, patients respond with varying efficacies due to multiple factors, and there is an urgent need to discover new treatment options to improve clinical outcomes. Cuproptosis is a newly characterized form of cell death. Copper causes cuproptosis by binding to lipid-acylated components of the tricarboxylic acid cycle, leading to protein aggregation, loss of iron-sulfur cluster proteins, and eventually proteotoxic stress. Targeting copper cytotoxicity and cuproptosis are considered potential options for treating oncological diseases. The synovial hypoxic environment and the presence of excessive glycolysis in multiple cells appear to act as inhibitors of cuproptosis, which can lead to excessive survival and proliferation of multiple immune cells, such as fibroblast-like synoviocytes, effector T cells, and macrophages, further mediating inflammation and bone destruction in RA. Therefore, in this study, we attempted to elaborate and summarize the linkage of cuproptosis and key genes regulating cuproptosis to the pathological mechanisms of RA and their effects on a variety of immune cells. This study aimed to provide a theoretical basis and support for translating preclinical and experimental results of RA to clinical protocols.

Topics: Humans; Arthritis, Rheumatoid; Copper; Inflammation; Synoviocytes; Synovitis; Apoptosis

PubMed: 35990673
DOI: 10.3389/fimmu.2022.930278

Review

Authors: Samuel Kemble, Adam P Croft

Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.

Topics: Animals; Arthritis; Arthritis, Rheumatoid; Biomarkers; Cell Communication; Disease Susceptibility; Fibroblasts; Gene Expression Regulation; Humans; Macrophages; Receptors, Notch; Recurrence; Signal Transduction; Synovial Membrane; Synoviocytes

PubMed: 34539648
DOI: 10.3389/fimmu.2021.715894

Authors: Di Liu, Ruiru Li, Siqi Xu...

Fibroblast-like synoviocytes (FLSs), play a key role in perpetuating synovial inflammation and bone erosion in rheumatoid arthritis (RA), however, the underlying mechanism(s) of RA FLSs activation and aggression remain unclear. Identifying endogenous proteins that selectively target FLSs is urgently needed. Here, we systematically identified that secreted modular calcium-binding protein 2 (SMOC2), was significantly increased in RA FLSs and synovial tissues. SMOC2 knockdown specifically regulated cytoskeleton remodeling and decreased the migration and invasion of RA FLSs. Mechanistically, cytoskeleton-related genes were significantly downregulated in RA FLSs with reduced SMOC2 expression, especially the motor protein myosin1c (MYO1C). SMOC2 controlled MYO1C expression by SRY-related high-mobility group box 4 (SOX4) and AlkB homolog 5 (ALKHB5) mediated-mA modification through transcriptional and post-transcriptional regulation. Furthermore, intra-articular Ad-shRNA-SMOC2 treatment attenuated synovial inflammation as well as bone and cartilage erosion in rats with collagen-induced arthritis (CIA). Our findings suggest that increased SMOC2 expression in FLSs may contribute to synovial aggression and joint destruction in RA. SMOC2 may serve as a potential target against RA. SMOC2-mediated regulation of the synovial migration and invasion in RA FLSs. In RA FLSs, SMOC2 is significantly increased, leading to the increased level of MYO1C via SOX4-mediated transcriptional regulation and ALKBH5-mediated mA modification, thereby causing cytoskeleton remodeling and promoting RA FLSs migration and invasion. The Figure was drawn by Figdraw.

Topics: Rats; Animals; Synoviocytes; Cells, Cultured; Signal Transduction; Arthritis, Rheumatoid; Fibroblasts; Cell Movement; Inflammation; Aggression; Cell Proliferation

PubMed: 36513634
DOI: 10.1038/s41419-022-05479-0