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Seminars in Arthritis and Rheumatism Feb 2024Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis (RA), 40% of patients show poor clinical response, and there... (Review)
Review
BACKGROUND
Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis (RA), 40% of patients show poor clinical response, and there is an imperative to unravel the molecular pathways and mechanisms underlying non-response and disease progression. 5-20% of RA individuals do not respond to all current medications including biologic and targeted therapies, which suggests that distinct pathogenic processes underlie multi-drug refractoriness.
OBJECTIVES
In this brief review we discuss advances from recent studies in precision medicine in rheumatoid arthritis.
METHODS
Bulk RNA-Sequencing of synovial biopsies from RA individuals combined with histology and deep clinical phenotyping has revealed substantial insights into divergent pathogenic pathways which lead to disease progression and illuminated mechanisms underlying failure to response to specific treatments. Biopsy-driven randomised controlled trials, such as R4RA and the forthcoming STRAP trial, have enabled the development of machine learning predictive models for predicting response to different therapies.
RESULTS
In the Pathobiology of Early Arthritis Cohort (PEAC), gene expression analysis showed that individuals could be classified into three gene expression subgroups which correlated with histopathotypes defined by histological markers: pauci-immune fibroid pathotype characterised by fibroblasts and an absence of immune inflammatory cells; diffuse-myeloid pathotype characterised by macrophage influx; and the lympho-myeloid pathotype delineated by the presence of B cells, but typically containing a complex inflammatory infiltrate with ectopic lymphoid structure formation. In the R4RA biopsy-driven randomised controlled trial, patients were randomised to either rituximab or tocilizumab. Comprehensive analysis of synovial biopsies pre/post-treatment identified gene signatures of response associated with pathogenic pathways which could be tracked over time. A group of true refractory patients were identified who had failed anti-TNF prior to the study (it was an entry criterion) and then subsequently failed both trial biologics during the trial. RNA-Seq analysis and digital spatial profiling identified specific cell types including DKK3 fibroblasts as being associated with the refractory state. We identified machine learning predictive models based on specific gene signatures which were able to predict future response to therapy as well as the refractory state.
CONCLUSIONS
RNA-sequencing of synovial biopsies has enabled substantial progress in understanding disease endotypes in RA and identifying synovial gene signatures which predict prognosis and future response to treatment.
Topics: Humans; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Arthritis, Rheumatoid; Disease Progression; RNA; Synovial Membrane; Randomized Controlled Trials as Topic
PubMed: 38008706
DOI: 10.1016/j.semarthrit.2023.152329 -
Stem Cell Research & Therapy Aug 2019Synovial-derived cells, found in the synovial membrane of human joints, were obtained by digestion of the synovial membrane and were subsequently expanded in vitro. The... (Review)
Review
Synovial-derived cells, found in the synovial membrane of human joints, were obtained by digestion of the synovial membrane and were subsequently expanded in vitro. The identity of synovial-derived cells has long been a topic of debate. The terms "type B synoviocytes," "fibroblast-like synoviocytes (FLS)," "synovium-derived mesenchymal stem cells (MSCs)," and "synovial fibroblasts (SF)" appeared in different articles related to human synovial-derived cells in various disease models, yet they seemed to be describing the same cell type. However, to date, there is no clear standard to distinguish these terms; thus, the hypothesis that they represent the same cell type is currently inconclusive. Therefore, this review aims to clarify the similarities and differences between these terms and to diffuse the chaotic nomenclature of synovial-derived cells.
Topics: Cells, Cultured; Fibroblasts; Humans; Mesenchymal Stem Cells; Synovial Membrane; Terminology as Topic
PubMed: 31426847
DOI: 10.1186/s13287-019-1359-x -
Journal of Anatomy Aug 2018The infrapatellar pad, a fibro-adipose tissue with peculiar microscopic and mechanical features, is gaining wide attention in the field of rheumatological research. The... (Review)
Review
The infrapatellar pad, a fibro-adipose tissue with peculiar microscopic and mechanical features, is gaining wide attention in the field of rheumatological research. The purpose of this descriptive review is to summarize the most recent published evidence on the anatomic, physiologic and biomechanical inter-relationship between the infrapatellar fat pad and the knee synovial membrane. As an extrasynovial tissue, the infrapatellar fat pad does not directly interact with the articular cartilage; based on its location in close contact with the synovial membrane, and due to the metabolic properties of adipose tissue, it may influence the behavior of the synovial membrane. In fact, considering evidence of macroscopic and microscopic anatomy, the infrapatellar fat pad is the site of insertion of the infrapatellar and medial synovial plicae. Also biochemically, there is much evidence highlighting the interaction among these two structures; in the case of inflammation, the mutual interplay is ascribable to the release of pro-inflammatory mediators stimulating the proliferation of inflammatory cells and promoting tissue modifications in both. All these assumptions could support the emerging idea that the infrapatellar fat pad and the synovial membrane may be considered a morpho-functional unit.
Topics: Adipose Tissue; Humans; Knee Joint; Synovial Membrane
PubMed: 29761471
DOI: 10.1111/joa.12820 -
RMD Open Jan 2022To integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective...
OBJECTIVES
To integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis.
METHODS
In this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed.
RESULTS
We identified four SF clusters with respective marker genes: SF ( ); SF ( ); SF (); SF () that correspond to lining ( SF) and sublining ( SF, + and SF) SF subsets. SF and + were most prominent in the fibroid while SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. SF correlated positively with disease severity parameters in the fibroid, SF in the lymphoid pathotype whereas SF showed negative association with disease severity in all pathotypes.
CONCLUSION
This study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.
Topics: Arthritis, Rheumatoid; Fibroblasts; Humans; Synovial Membrane
PubMed: 34987094
DOI: 10.1136/rmdopen-2021-001949 -
Macrophages in the synovial lining niche initiate neutrophil recruitment and articular inflammation.The Journal of Experimental Medicine Aug 2023The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In...
The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In this study, we employ state-of-the-art confocal microscopy and image analysis in a systemic, whole-organ, and quantitative way to present evidence that synovial inflammation begins with the activation of lining macrophages. We show that lining, but not sublining macrophages phagocytose immune complexes containing the model antigen. Using the antigen-induced arthritis (AIA) model, we demonstrate that on recognition of antigen-antibody complexes, lining macrophages undergo significant activation, which is dependent on interferon regulatory factor 5 (IRF5), and produce chemokines, most notably CXCL1. Consequently, at the onset of inflammation, neutrophils are preferentially recruited in the vicinity of antigen-laden macrophages in the synovial lining niche. As inflammation progresses, neutrophils disperse across the whole synovium and form swarms in synovial sublining during resolution. Our study alters the paradigm of lining macrophages as immunosuppressive cells to important instigators of synovial inflammation.
Topics: Humans; Neutrophil Infiltration; Arthritis; Macrophages; Synovial Membrane; Inflammation; Antigens
PubMed: 37115585
DOI: 10.1084/jem.20220595 -
BioMed Research International 2019Osteoarthritis (OA) is the most common form of joint disease and a major cause of pain and disability in the adult population. Interestingly, there are patients with... (Review)
Review
Osteoarthritis (OA) is the most common form of joint disease and a major cause of pain and disability in the adult population. Interestingly, there are patients with symptomatic OA displaying pain, while patients with asymptomatic OA that do not experience pain but show radiographic signs of joint damage. Pain is a complex experience integrating sensory, affective, and cognitive processes related to several peripheral and central nociceptive factors besides inflammation. During the last years, the role of infrapatellar fat pad (IFP), other than the synovial membrane, has been investigated as a potential source of pain in OA. Interestingly, new findings suggest that IFP and synovial membrane might act as a functional unit in OA pathogenesis and pain. The present review discuss the role of IFP and synovial membrane in the development of OA, with a particular focus on pain onset and the possible involved mediators that may play a role in OA pathology and pain mechanisms. Inflammation of IFP and synovial membrane may drive peripheral and central sensitization in KOA. Since sensitization is associated with pain severity in knee OA and may potentially contribute to the transition from acute to chronic, persistent pain in knee OA, preventing sensitization would be a potentially effective and novel means of preventing worsening of pain in knee OA.
Topics: Adipose Tissue; Animals; Humans; Inflammation; Knee Joint; Osteoarthritis, Knee; Pain; Patella; Synovial Membrane
PubMed: 31049352
DOI: 10.1155/2019/6390182 -
International Journal of Molecular... Feb 2023Osteoarthritis (OA) is a chronic, progressive, severely debilitating, and multifactorial joint disease that is recognized as the most common type of arthritis. During... (Review)
Review
Osteoarthritis (OA) is a chronic, progressive, severely debilitating, and multifactorial joint disease that is recognized as the most common type of arthritis. During the last decade, it shows an incremental global rise in prevalence and incidence. The interaction between etiologic factors that mediate joint degradation has been explored in numerous studies. However, the underlying processes that induce OA remain obscure, largely due to the variety and complexity of these mechanisms. During synovial joint dysfunction, the osteochondral unit undergoes cellular phenotypic and functional alterations. At the cellular level, the synovial membrane is influenced by cartilage and subchondral bone cleavage fragments and extracellular matrix (ECM) degradation products from apoptotic and necrotic cells. These "foreign bodies" serve as danger-associated molecular patterns (DAMPs) that trigger innate immunity, eliciting and sustaining low-grade inflammation in the synovium. In this review, we explore the cellular and molecular communication networks established between the major joint compartments-the synovial membrane, cartilage, and subchondral bone of normal and OA-affected joints.
Topics: Humans; Cartilage, Articular; Osteoarthritis; Joints; Synovial Membrane; Bone and Bones; Inflammation
PubMed: 36835530
DOI: 10.3390/ijms24044120 -
Stem Cell Research & Therapy Oct 2014Mesenchymal stem cells (MSCs) have the ability to differentiate into osteoblasts, chondroblasts, adipocytes, and even myoblasts. Most studies have focused on finding... (Review)
Review
Mesenchymal stem cells (MSCs) have the ability to differentiate into osteoblasts, chondroblasts, adipocytes, and even myoblasts. Most studies have focused on finding MSCs in different parts of the body for medical treatment. Every joint structure, including bone, joint fat, articular cartilage, and synovium, potentially contains resident MSCs. Recently, a progenitor cell population has been found in synovial fluid and showed similarities with both bone marrow and synovial membrane MSCs. Synovial fluid MSCs have been studied in healthy persons and osteoarthritic patients in order to explore its potential for treatment of some orthopedic disorders. Here, we briefly review the current knowledge on synovial fluid MSCs, their origin, relation to some orthopedic diseases, and future applications.
Topics: Cell Differentiation; Cells, Cultured; Humans; Mesenchymal Stem Cells; Synovial Fluid; Synovial Membrane
PubMed: 25688673
DOI: 10.1186/scrt501 -
Frontiers in Endocrinology 2023Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and... (Review)
Review
Osteoarthritis (OA) is a disabling disease with significant morbidity worldwide. OA attacks the large synovial joint, including the peripheral joints and temporomandibular joint (TMJ). As a representative of peripheral joint OA, knee OA shares similar symptoms with TMJ OA. However, these two joints also display differences based on their distinct development, anatomy, and physiology. Extracellular vesicles (EVs) are phospholipid bilayer nanoparticles, including exosomes, microvesicles, and apoptotic bodies. EVs contain proteins, lipids, DNA, micro-RNA, and mRNA that regulate tissue homeostasis and cell-to-cell communication, which play an essential role in the progression and treatment of OA. They are likely to partake in mechanical response, extracellular matrix degradation, and inflammatory regulation during OA. More evidence has shown that synovial fluid and synovium-derived EVs may serve as OA biomarkers. More importantly, mesenchymal stem cell-derived EV shows a therapeutic effect on OA. However, the different function of EVs in these two joints is largely unknown based on their distinct biological characteristic. Here, we reviewed the effects of EVs in OA progression and compared the difference between the knee joint and TMJ, and summarized their potential therapeutic role in the treatment of OA.
Topics: Humans; Osteoarthritis; Temporomandibular Joint; Extracellular Vesicles; Synovial Membrane; Synovial Fluid
PubMed: 36950682
DOI: 10.3389/fendo.2023.1158744 -
Osteoarthritis and Cartilage Sep 2022Osteoarthritis (OA) affects the entire joint, initially with a low degree of inflammation. Synovitis is correlated with the severity of OA clinical symptoms and... (Review)
Review
BACKGROUND
Osteoarthritis (OA) affects the entire joint, initially with a low degree of inflammation. Synovitis is correlated with the severity of OA clinical symptoms and cartilage degradation. The synovial lymphatic system (SLS) plays a prominent role in clearing macromolecules within the joint, including the pro-inflammatory cytokines in arthritic status. Scattered evidence shows that impaired SLS drainage function leads to the accumulation of inflammatory factors in the joint and aggravates the progression of OA, and the role of SLS function in OA is less studied.
DESIGN
This review summarizes the current understanding of synovial lymphatic function in OA progression and potential regulatory pathways and aims to provide a framework of knowledge for the development of OA treatments targeting lymphatic structure and functions.
RESULTS
SLS locates in the subintima layer of the synovium and consists of lymphatic capillaries and lymphatic collecting vessels. Vascular endothelial growth factor C (VEGF-C) is the most critical regulating factor of lymphatic endothelial cells (LECs) and SLS. Nitric oxide production-induced impairment of lymphatic muscle cells (LMCs) and contractile function may attribute to drainage dysfunction. Preclinical evidence suggests that promoting lymphatic drainage may help restore intra-articular homeostasis to attenuate the progression of OA.
CONCLUSION
SLS is actively involved in the homeostatic maintenance of the joint. Understanding the drainage function of the SLS at different stages of OA development is essential for further design of therapies targeting the function of these vessels.
Topics: Endothelial Cells; Humans; Lymphatic System; Lymphatic Vessels; Osteoarthritis; Synovial Membrane; Vascular Endothelial Growth Factor C
PubMed: 35487439
DOI: 10.1016/j.joca.2022.04.003