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Arthritis Research & Therapy Feb 2017Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage,... (Review)
Review
Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and (increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically.
Topics: Cartilage, Articular; Cytokines; Disease Progression; Humans; Inflammation Mediators; Knee Joint; Models, Biological; Osteoarthritis; Synovial Membrane; Synovitis
PubMed: 28148295
DOI: 10.1186/s13075-017-1229-9 -
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 Aug 2017The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the... (Review)
Review
The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis and stratification, as well as in predicting disease course and treatment response.
Topics: Arthritis, Rheumatoid; Biomarkers; Biomedical Research; Humans; Synovial Fluid; Synovial Membrane
PubMed: 28701760
DOI: 10.1038/nrrheum.2017.115 -
Biological & Pharmaceutical Bulletin 2019Temporomandibular disorders (TMD) are a common stomatognathic disease affecting all age groups. Patients with internal derangement (ID) or osteoarthritis (OA) of... (Review)
Review
Temporomandibular disorders (TMD) are a common stomatognathic disease affecting all age groups. Patients with internal derangement (ID) or osteoarthritis (OA) of temporomandibular joint (TMJ) often have TMJ synovitis. When TMJ synovial membrane is damaged, many inflammatory cytokines are produced and secreted from TMJ synoviocytes to synovial fluid of TMJ. It has been widely reported that many kinds of biologic factors are produced from TMJ synoviocytes stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. One of the major symptoms of TMD is pain of the TMJ. Many study groups have studied relations between the development of TMJ pain and biologic factors secreted into synovial fluid of TMJ. Here, we summarize previous reports trying to elucidate this correlation. On the other hand, it has been reported that a new molecular mechanism of IL-1beta secretion called inflammasome is involved in several diseases with sterile inflammation. Because TMJ synovitis with ID and OA of TMJ is also sterile inflammation, inflammasome may be involved in the development of TMJ synovial inflammation. This review describes some molecular mechanisms underlying inflammation in TMJ, especially in TMJ synovitis, which may be useful for the development of new therapies against TMD.
Topics: Animals; Cytokines; Humans; Pain; Synovial Membrane; Synovitis; Temporomandibular Joint; Temporomandibular Joint Disorders
PubMed: 30930413
DOI: 10.1248/bpb.b18-00442 -
Bone Aug 2012Research into the pathophysiology of osteoarthritis (OA) has focused on cartilage and peri-articular bone, but there is increasing recognition that OA affects all of the... (Review)
Review
Research into the pathophysiology of osteoarthritis (OA) has focused on cartilage and peri-articular bone, but there is increasing recognition that OA affects all of the joint tissues, including the synovium (SM). Under normal physiological conditions the synovial lining consists of a thin layer of cells with phenotypic features of macrophages and fibroblasts. These cells and the underlying vascularized connective tissue stroma form a complex structure that is an important source of synovial fluid (SF) components that are essential for normal cartilage and joint function. The histological changes observed in the SM in OA generally include features indicative of an inflammatory "synovitis"; specifically they encompass a range of abnormalities, such as synovial lining hyperplasia, infiltration of macrophages and lymphocytes, neoangiogenesis and fibrosis. The pattern of synovial reaction varies with disease duration and associated metabolic and structural changes in other joint tissues. Imaging modalities including magnetic resonance (MRI) and ultrasound (US) have proved useful in detecting and quantifying synovial abnormalities, but individual studies have varied in their methods of evaluation. Despite these differences, most studies have concluded that the presence of synovitis in OA is associated with more severe pain and joint dysfunction. In addition, synovitis may be predictive of faster rates of cartilage loss in certain patient populations. Recent studies have provided insights into the pathogenic mechanisms underlying the development of synovitis in OA. Available evidence suggests that the inflammatory process involves engagement of Toll-like receptors and activation of the complement cascade by degradation products of extracellular matrices of cartilage and other joint tissues. The ensuing synovial reaction can lead to synthesis and release of a wide variety of cytokines and chemokines. Some of these inflammatory mediators are detected in joint tissues and SF in OA and have catabolic effects on chondrocytes. These inflammatory mediators represent potential targets for therapeutic interventions designed to reduce both symptoms and structural joint damage in OA. This article is part of a Special Issue entitled "Osteoarthritis".
Topics: Animals; Disease Progression; Humans; Inflammation Mediators; Osteoarthritis; Signal Transduction; Synovial Membrane; Synovitis
PubMed: 22387238
DOI: 10.1016/j.bone.2012.02.012 -
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 -
Clinics in Geriatric Medicine May 2022Chronic pain is a substantial personal and societal burden worldwide. Osteoarthritis (OA) is one of the leading causes of chronic pain and is increasing in prevalence in... (Review)
Review
Chronic pain is a substantial personal and societal burden worldwide. Osteoarthritis (OA) is one of the leading causes of chronic pain and is increasing in prevalence in accordance with a global aging population. In addition to affecting patients' physical lives, chronic pain also adversely affects patients' mental wellbeing. However, there remain no pharmacologic interventions to slow down the progression of OA and pain-alleviating therapies are largely unsuccessful. The presence of low-level inflammation in OA has been recognized for many years as a major pathogenic driver of joint damage. Inflammatory mechanisms can occur locally in joint tissues, such as the synovium, within the sensory nervous system, as well as systemically, caused by modifiable and unmodifiable factors. Understanding how inflammation may contribute to, and modify pain in OA will be instrumental in identifying new druggable targets for analgesic therapies. In this narrative review, we discuss recent insights into inflammatory mechanisms in OA pain. We discuss how local inflammation in the joint can contribute to mechanical sensitization and to the structural neuroplasticity of joint nociceptors, through pro-inflammatory factors such as nerve growth factor, cytokines, and chemokines. We consider the role of synovitis, and the amplifying mechanisms of neuroimmune interactions. We then explore emerging evidence around the role of neuroinflammation in the dorsal root ganglia and dorsal horn. Finally, we discuss how systemic inflammation associated with obesity may modify OA pain and suggest future research directions.
Topics: Aged; Chronic Pain; Humans; Inflammation; Osteoarthritis; Synovial Membrane; Synovitis
PubMed: 35410677
DOI: 10.1016/j.cger.2021.11.013 -
Cellular and Molecular Life Sciences :... Apr 2022Osteoarthritis (OA) synovial membrane is mainly characterized by low-grade inflammation, hyperplasia with increased cell proliferation and fibrosis. We previously...
Osteoarthritis (OA) synovial membrane is mainly characterized by low-grade inflammation, hyperplasia with increased cell proliferation and fibrosis. We previously underscored a critical role for CEMIP in fibrosis of OA cartilage. However, its role in OA synovial membrane remains unknown. An in vitro model with fibroblast-like synoviocytes from OA patients and an in vivo model with collagenase-induced OA mice were used to evaluate CEMIP-silencing effects on inflammation, hyperplasia and fibrosis. Our results showed that i. CEMIP expression was increased in human and mouse inflamed synovial membrane; ii. CEMIP regulated the inflammatory response pathway and inflammatory cytokines production in vitro and in vivo; iii. CEMIP induced epithelial to mesenchymal transition pathway and fibrotic markers in vitro and in vivo; iv. CEMIP increased cell proliferation and synovial hyperplasia; v. CEMIP expression was increased by inflammatory cytokines and by TGF-β signaling; vi. anti-fibrotic drugs decreased CEMIP expression. All these findings highlighted the central role of CEMIP in OA synovial membrane development and underscored that targeting CEMIP could be a new therapeutic approach.
Topics: Animals; Cytokines; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Hyaluronoglucosaminidase; Hyperplasia; Inflammation; Mice; Osteoarthritis; Synovial Membrane
PubMed: 35474501
DOI: 10.1007/s00018-022-04282-6 -
Clinical and Translational Medicine Apr 2023Osteoarthritis (OA), a multifaceted condition, poses a significant challenge for the successful clinical development of therapeutics due to heterogeneity. However,...
BACKGROUND
Osteoarthritis (OA), a multifaceted condition, poses a significant challenge for the successful clinical development of therapeutics due to heterogeneity. However, classifying molecular endotypes of OA pathogenesis could provide invaluable phenotype-directed routes for stratifying subgroups of patients for targeted therapeutics, leading to greater chances of success in trials. This study establishes endotypes in OA soft joint tissue driven by obesity in both load-bearing and non-load bearing joints.
METHODS
Hand, hip, knee and foot joint synovial tissue was obtained from OA patients (n = 32) classified as obese (BMI > 30) or normal weight (BMI 18.5-24.9). Isolated fibroblasts (OA SF) were assayed by Olink proteomic panel, seahorse metabolic flux assay, Illumina's NextSeq 500 bulk and Chromium 10X single cell RNA-sequencing, validated by Luminex and immunofluorescence.
RESULTS
Targeted proteomic, metabolic and transcriptomic analysis found the inflammatory landscape of OA SFs are independently impacted by obesity, joint loading and anatomical site with significant heterogeneity between obese and normal weight patients, confirmed by bulk RNAseq. Further investigation by single cell RNAseq identified four functional molecular endotypes including obesity specific subsets defined by an inflammatory endotype related to immune cell regulation, fibroblast activation and inflammatory signaling, with up-regulated CXCL12, CFD and CHI3L1 expression. Luminex confirmed elevated chitase3-like-1(229.5 vs. 49.5 ng/ml, p < .05) and inhibin (20.6 vs. 63.8 pg/ml, p < .05) in obese and normal weight OA SFs, respectively. Lastly, we find SF subsets in obese patients spatially localise in sublining and lining layers of OA synovium and can be distinguished by differential expression of the transcriptional regulators MYC and FOS.
CONCLUSION
These findings demonstrate the significance of obesity in changing the inflammatory landscape of synovial fibroblasts in both load bearing and non-load bearing joints. Describing multiple heterogeneous OA SF populations characterised by specific molecular endotypes, which drive heterogeneity in OA disease pathogenesis. These molecular endotypes may provide a route for the stratification of patients in clinical trials, providing a rational for the therapeutic targeting of specific SF subsets in specific patient populations with arthritic conditions.
Topics: Humans; Proteomics; Synovial Membrane; Osteoarthritis; Obesity; Fibroblasts
PubMed: 37006170
DOI: 10.1002/ctm2.1232 -
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