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International Journal of Molecular... Mar 2023Osteoarthritis (OA) is a chronic disease and the most common orthopedic disorder. A vast majority of the social OA burden is related to hips and knees. The prevalence of... (Review)
Review
Osteoarthritis (OA) is a chronic disease and the most common orthopedic disorder. A vast majority of the social OA burden is related to hips and knees. The prevalence of knee OA varied across studies and such differences are reflected by the heterogeneity of data reported by studies conducted worldwide. A complete understanding of the pathogenetic mechanisms underlying this pathology is essential. The OA inflammatory process starts in the synovial membrane with the activation of the immune system, involving both humoral and cellular mediators. A crucial role in this process is played by the so-called "damage-associated molecular patterns" (DAMPs). Mesenchymal stem cells (MSCs) may be a promising option among all possible therapeutic options. However, many issues are still debated, such as the best cell source, their nature, and the right amount. Further studies are needed to clarify the remaining doubts. This review provides an overview of the most recent and relevant data on the molecular mechanism of cartilage damage in knee OA, including current therapeutic approaches in regenerative medicine.
Topics: Humans; Osteoarthritis, Knee; Synovial Membrane; Mesenchymal Stem Cells; Mesenchymal Stem Cell Transplantation
PubMed: 37047377
DOI: 10.3390/ijms24076405 -
Nature Reviews. Rheumatology May 2022Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with... (Review)
Review
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 -
Current Opinion in Pharmacology Dec 2022Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the... (Review)
Review
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 -
Best Practice & Research. Clinical... Mar 2022Rheumatoid arthritis is an autoimmune disease that causes significant morbidity. Application of cellular profiling techniques such as single-cell transcriptomics and... (Review)
Review
Rheumatoid arthritis is an autoimmune disease that causes significant morbidity. Application of cellular profiling techniques such as single-cell transcriptomics and spatial transcriptomics has uncovered novel pathogenic cell types in RA joint tissues and revealed marked heterogeneity in the cellular composition among RA patients. Together, these insights provide exciting opportunities to translate discoveries into precision medicine in RA. The present review aims to highlight novel insights into RA pathology and discuss key steps needed to translate these discoveries into actionable changes in clinical practice. We review the efforts to identify surrogate biomarkers that could be used to predict RA synovial tissue phenotypes and the corresponding responses to therapy. Finally, we discuss the opportunity to develop novel patient-derived organoid systems as a platform for therapeutic target validation.
Topics: Arthritis, Rheumatoid; Biomarkers; Humans; Precision Medicine; Synovial Membrane
PubMed: 35248489
DOI: 10.1016/j.berh.2022.101742 -
Nature Reviews. Rheumatology Jun 2020Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium... (Review)
Review
Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.
Topics: Arthritis, Rheumatoid; B-Lymphocytes; Bone Resorption; Cadherins; Cartilage, Articular; DNA Methylation; Endothelial Cells; Epigenesis, Genetic; Fibroblasts; Humans; Macrophages; Molecular Targeted Therapy; Monocytes; Neovascularization, Pathologic; Osteogenesis; Protein Tyrosine Phosphatases; Synovial Membrane; Synoviocytes; T-Lymphocytes
PubMed: 32393826
DOI: 10.1038/s41584-020-0413-5 -
ELife May 2023Obesity has always been considered a significant risk factor in osteoarthritis (OA) progression, but the underlying mechanism of obesity-related inflammation in OA...
Obesity has always been considered a significant risk factor in osteoarthritis (OA) progression, but the underlying mechanism of obesity-related inflammation in OA synovitis remains unclear. The present study found that synovial macrophages infiltrated and polarized in the obesity microenvironment and identified the essential role of M1 macrophages in impaired macrophage efferocytosis using pathology analysis of obesity-associated OA. The present study revealed that obese OA patients and mice showed a more pronounced synovitis and enhanced macrophage infiltration in synovial tissue, accompanied by dominant M1 macrophage polarization. Obese OA mice had a more severe cartilage destruction and increased levels of synovial apoptotic cells (ACs) than OA mice in the control group. Enhanced M1-polarized macrophages in obese synovium decreased growth arrest-specific 6 (GAS6) secretion, resulting in impaired macrophage efferocytosis in synovial ACs. Intracellular contents released by accumulated ACs further triggered an immune response and lead to a release of inflammatory factors, such as TNF-α, IL-1β, and IL-6, which induce chondrocyte homeostasis dysfunction in obese OA patients. Intra-articular injection of GAS6 restored the phagocytic capacity of macrophages, reduced the accumulation of local ACs, and decreased the levels of TUNEL and Caspase-3 positive cells, preserving cartilage thickness and preventing the progression of obesity-associated OA. Therefore, targeting macrophage-associated efferocytosis or intra-articular injection of GAS6 is a potential therapeutic strategy for obesity-associated OA.
Topics: Animals; Mice; Macrophages; Obesity; Osteoarthritis; Synovial Membrane; Synovitis; Humans
PubMed: 37144868
DOI: 10.7554/eLife.83069 -
Annals of the Rheumatic Diseases Feb 2023Synovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and...
OBJECTIVES
Synovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and molecular mechanisms in PTOA synovium. We aimed to describe synovial cell populations and their dynamics in PTOA, with a focus on fibroblasts. We also sought to define mechanisms of synovial Wnt/β-catenin signalling, given its emerging importance in arthritis.
METHODS
We subjected mice to non-invasive anterior cruciate ligament rupture as a model of human joint injury. We performed single-cell RNA-sequencing to assess synovial cell populations, subjected Wnt-GFP reporter mice to joint injury to study Wnt-active cells, and performed intra-articular injections of the Wnt agonist R-spondin 2 (Rspo2) to assess whether gain of function induced pathologies characteristic of PTOA. Lastly, we used cultured fibroblasts, macrophages and chondrocytes to study how Rspo2 orchestrates crosstalk between joint cell types.
RESULTS
We uncovered seven distinct functional subsets of synovial fibroblasts in healthy and injured synovium, and defined their temporal dynamics in early and established PTOA. Wnt/β-catenin signalling was overactive in PTOA synovium, and Rspo2 was strongly induced after injury and secreted exclusively by Prg4 lining fibroblasts. Trajectory analyses predicted that Prg4 lining fibroblasts arise from a pool of Dpp4+ mesenchymal progenitors in synovium, with SOX5 identified as a potential regulator of this emergence. We also showed that Rspo2 orchestrated pathological crosstalk between synovial fibroblasts, macrophages and chondrocytes.
CONCLUSIONS
Synovial fibroblasts assume distinct functional identities during PTOA in mice, and Prg4 lining fibroblasts secrete Rspo2 that may drive pathological joint crosstalk after injury.
Topics: Animals; Humans; Mice; Chondrocytes; Fibroblasts; Osteoarthritis; Synovial Membrane; Wnt Signaling Pathway; Thrombospondins
PubMed: 36175067
DOI: 10.1136/ard-2022-222773 -
Frontiers in Immunology 2021Single-cell RNA sequencing (scRNA-seq) technology can analyze the transcriptome expression level of cells with high-throughput from the single cell level, fully show the... (Review)
Review
Single-cell RNA sequencing (scRNA-seq) technology can analyze the transcriptome expression level of cells with high-throughput from the single cell level, fully show the heterogeneity of cells, and provide a new way for the study of multicellular biological heterogeneity. Synovitis is the pathological basis of rheumatoid arthritis (RA). Synovial fibroblasts (SFs) and synovial macrophages are the core target cells of RA, which results in the destruction of articular cartilage, as well as bone. Recent scRNA-seq technology has made breakthroughs in the differentiation and development of two types of synovial cells, identification of subsets, functional analysis, and new therapeutic targets, which will bring remarkable changes in RA treatment.
Topics: Arthritis, Rheumatoid; Fibroblasts; Humans; Macrophages; Sequence Analysis, RNA; Single-Cell Analysis; Synovial Membrane
PubMed: 34349767
DOI: 10.3389/fimmu.2021.709178 -
Frontiers in Immunology 2021Rheumatoid arthritis (RA) is a common, chronic, systemic autoimmune disease, and its clinical features are the proliferation of joint synovial tissue, the formation of... (Review)
Review
Rheumatoid arthritis (RA) is a common, chronic, systemic autoimmune disease, and its clinical features are the proliferation of joint synovial tissue, the formation of pannus and the destruction of cartilage. The global incidence of RA is about 1%, and it is more common in women. The basic feature of RA is the body's immune system disorders, in which autoreactive CD4T cells, pathogenic B cells, M1 macrophages, inflammatory cytokines, chemokines and autoantibodies abnormally increase in the body of RA patients B cell depletion therapy has well proved the important role of B cells in the pathogenesis of RA, and the treatment of RA with B cells as a target has also been paid more and more attention. Although the inflammatory indicators in RA patients receiving B-cell depletion therapy have been significantly improved, the risk of infection and cancer has also increased, which suggests that we need to deplete pathogenic B cells instead of all B cells. However, at present we cannot distinguish between pathogenic B cells and protective B cells in RA patients. In this review, we explore fresh perspectives upon the roles of B cells in the occurrence, development and treatment of RA.
Topics: Animals; Arthritis, Rheumatoid; B-Lymphocytes; Humans; Immune Tolerance; Synovial Membrane
PubMed: 34650569
DOI: 10.3389/fimmu.2021.750753 -
Frontiers in Immunology 2021Rheumatoid arthritis is an autoimmune disease that exhibits significant clinical heterogeneity. There are various treatments for rheumatoid arthritis, including... (Review)
Review
Rheumatoid arthritis is an autoimmune disease that exhibits significant clinical heterogeneity. There are various treatments for rheumatoid arthritis, including disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and inflammatory cytokine inhibitors (ICI), typically associated with differentiated clinical effects and characteristics. Personalized responsiveness is observed to the standard treatment due to the pathophysiological heterogeneity in rheumatoid arthritis, resulting in an overall poor prognosis. Understanding the role of individual variation in cellular and molecular mechanisms related to rheumatoid arthritis will considerably improve clinical care and patient outcomes. In this review, we discuss the source of pathophysiological heterogeneity derived from genetic, molecular, and cellular heterogeneity and their possible impact on precision medicine and personalized treatment of rheumatoid arthritis. We provide emphasized description of the heterogeneity derived from mast cells, monocyte cell, macrophage fibroblast-like synoviocytes and, interactions within immune cells and with inflammatory cytokines, as well as the potential as a new therapeutic target to develop a novel treatment approach. Finally, we summarize the latest clinical trials of treatment options for rheumatoid arthritis and provide a suggestive framework for implementing preclinical and clinical experimental results into clinical practice.
Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Cytokines; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Immune System; Inflammation Mediators; Phenotype; Signal Transduction; Synovial Membrane
PubMed: 34899757
DOI: 10.3389/fimmu.2021.790122