Fibroblast Like Synovial Cell Subsets in Rheumatoid Arthritis

Fibroblasts like synoviocytes (FLS) play several significant roles in rheumatoid arthritis (RA) pathophysiology. This chapter will describe known roles of FLS in disease initiation, joint inflammation, disease persistence and joint destruction. It will describe the newly characterized subsets of FLS based on single cell RNA sequencing studies, and their association to specific aspects of the disease. Finally, we will discuss the future of targeting FLS in the treatment of RA. The FLS in the synovial lining layer are identified by surface complement decay-accelerating factor (CD55) along with lubricin and metallopeptidase expression. Pathological activation of this lining layer subset result in bone and cartilage damage in mice. FLS of the sublining layer are often characterized by THY1 expression, but recent studies have highlighted a heterogeneity where several distinct subsets are identified by additional markers. Sublining FLS expressing human leukocyte antigen-DRA (HLA-DRA) produce C-X-C motif chemokine 12 (CXCL12) and receptor activator of nuclear factor-κB ligand (RANKL) and seems to constitute a pro-inflammatory subset that is associated with inflammation and tertiary lymphoid structures. Another subset of FLS characterized by CD34 expression may discriminate a common progenitor fibroblast subset. Taken together, studies isolating and characterizing gene expression in synovial FLS report both associations of unknown importance and markers that may impose protective or destructive features. This supports evidence of FLS as active players in RA pathology capable of cellular recruitment, local cellular crosstalk and promotion of joint destruction. These discoveries may serve as an atlas for synovial activation in RA and have identified several potential fibroblast markers for the development of targeted treatment.

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Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview

Journal of Clinical Medicine ◽

10.3390/jcm10061241 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1241

Author(s):

Yoshiya Tanaka

Keyword(s):

Rheumatoid Arthritis ◽

Structural Damage ◽

Kinase Inhibitors ◽

Joint Destruction ◽

Joint Damage ◽

Nuclear Factor Κb ◽

Cartilage Destruction ◽

Janus Kinase ◽

Systemic Autoimmune Disease ◽

And Cartilage

In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.

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Fibroblasts and mesenchymal cells

Oxford Textbook of Rheumatology ◽

10.1093/med/9780199642489.003.0051 ◽

2013 ◽

pp. 379-385

Author(s):

Andrew Filer ◽

Maria Juarez ◽

Christopher Buckley

Keyword(s):

Rheumatoid Arthritis ◽

Wound Healing ◽

Joint Destruction ◽

Joint Inflammation ◽

Synovial Fibroblasts ◽

Mesenchymal Cells ◽

Structure And Function ◽

Epigenetic Programming ◽

Disease Initiation ◽

And Function

In order to understand and explore the function and roles of fibroblasts, it is necessary to understand their lineage relationships to other mesenchymal cells. Fibroblasts are ubiquitous non-epithelial, non-endothelial, and non-haematopoietic adherent cells that have the capacity to produce and remodel extracellular matrix. In addition to their well-known ’landscaping’ function which determines the unique structure and function of different organs, they play an important role in wound healing, immune tolerance, and disease. In cancer, epithelial-stromal interactions have been implicated in disease initiation and progression. In rheumatoid arthritis, synovial fibroblasts at diseased sites become persistently activated and behave abnormally, orchestrating joint inflammation and contributing to joint destruction. Recent evidence suggests that the activated phenotype of fibroblasts in pathology may result from epigenetic programming, which is becoming a major focus for development of new therapeutics.

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Elevated APE1/Ref-1 Levels of Synovial Fluids in Patients with Rheumatoid Arthritis: Reflection of Disease Activity

Journal of Clinical Medicine ◽

10.3390/jcm10225324 ◽

2021 ◽

Vol 10 (22) ◽

pp. 5324

Author(s):

In Seol Yoo ◽

Yu-Ran Lee ◽

Seong Wook Kang ◽

Jinhyun Kim ◽

Hee-Kyoung Joo ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Disease Activity Score ◽

Inflammatory Responses ◽

Joint Destruction ◽

Joint Inflammation ◽

Joint Disease ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Control ◽

The Relationship

There is growing evidence that apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) regulates inflammatory responses. Rheumatoid arthritis (RA) is an autoimmune disease, which is characterized with synovitis and joint destruction. Therefore, this study was planned to investigate the relationship between APE1/Ref-1 and RA. Serum and synovial fluid (SF) were collected from 46 patients with RA, 45 patients with osteoarthritis (OA), and 30 healthy control (HC) patients. The concentration of APE1/Ref-1 in serum or SF was measured using the sandwich enzyme-linked immunosorbent assay (ELISA). The disease activity in RA patients was measured using the 28-joint disease activity score (DAS28). The serum APE1/Ref-1 levels in RA patients were significantly increased compared to HC and OA patients (0.44 ± 0.39 ng/mL for RA group vs. 0.19 ± 0.14 ng/mL for HC group, p < 0.05 and vs. 0.19 ± 0.11 ng/mL for OA group, p < 0.05). Likewise, the APE1/Ref-1 levels of SF in RA patients were also significantly increased compared to OA patients (0.68 ± 0.30 ng/mL for RA group vs. 0.31 ± 0.12 ng/mL for OA group, p < 0.001). The APE1/Ref-1 concentration in SF of RA patients was positively correlated with DAS28. Thus, APE1/Ref-1 may reflect the joint inflammation and be associated with disease activity in RA.

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Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction

RMD Open ◽

10.1136/rmdopen-2020-001249 ◽

2020 ◽

Vol 6 (2) ◽

pp. e001249

Author(s):

Yoshiya Tanaka ◽

Satoshi Soen ◽

Naoki Ishiguro ◽

Hisashi Yamanaka ◽

Toshiyuki Yoneda ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Bone Erosion ◽

Joint Destruction ◽

Nuclear Factor Κb ◽

Phase Iii ◽

Concomitant Treatment ◽

Double Blind ◽

Radiographic Damage ◽

Interaction Factor

ObjectivesTo clarify which rheumatoid arthritis (RA) patients benefit most from the anti-receptor activator of nuclear factor-κB ligand antibody denosumab to reduce the progression of joint destruction.MethodsWe pooled patient data from the 12-month, double-blind, placebo-controlled DRIVE (phase II) and DESIRABLE (phase III) studies. In DRIVE, concomitant treatment was limited to methotrexate, salazosulfapyridine and bucillamine. In DESIRABLE, patients could receive any disease-modifying antirheumatic drug. RA patients were randomised to denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or placebo. Efficacy was assessed by van der Heijde-modified total Sharp score (mTSS), bone erosion score (ES) and joint space narrowing score (JSNS). Change in mTSS was assessed in subgroups stratified by risk factors for radiographic damage if the interaction factor was significant.ResultsThe pooled analysis included 909 patients. Denosumab reduced worsening of mTSS (mean (SD)) at 12 months in the Q6M (0.88 (3.30), p=0.0024) and Q3M (0.66 (2.16), p=0.0002) groups versus placebo (1.50 (3.73)). This reduction in mTSS progression was due to the change in ES (Q6M, 0.44 (1.89), p=0.0006; Q3M, 0.20 (0.86), p<0.0001) versus placebo (0.98 (2.54)); no effect was observed on JSNS. Anti-cyclic citrullinated peptide (CCP) antibodies, glucocorticoid use and baseline ES showed a significant interaction. Denosumab was particularly effective in patients who were anti-CCP antibody positive (p<0.05). Changes in mTSS versus placebo were observed in all denosumab dose groups, regardless of glucocorticoid use and baseline ES.ConclusionsDenosumab broadly reduced the progression of joint destruction in RA patients with risk factors for radiographic damage such as especially anti-CCP antibody positivity.

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The role of RANK ligand/osteoprotegerin in rheumatoid arthritis

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x12438080 ◽

2012 ◽

Vol 4 (4) ◽

pp. 225-233 ◽

Cited By ~ 59

Author(s):

Piet Geusens

Keyword(s):

Rheumatoid Arthritis ◽

Bone Resorption ◽

Bone Loss ◽

Bone Destruction ◽

Joint Inflammation ◽

Nuclear Factor Κb ◽

Coupling Factor ◽

Essential Components ◽

Bone Edema ◽

Magnetic Resonance Imaging Mri

In the complex system of bone remodeling, the receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) pathway is the coupling factor between bone formation and bone resorption. RANKL binds to the RANK receptor of pre-osteoclasts and mature osteoclasts and stimulates their activation and differentiation. The production of RANKL/OPG by osteoblasts is influenced by hormones, growth factors and cytokines, which each have a different effect on the production of RANKL and OPG. Ultimately, the balance between RANKL and OPG determines the degree of proliferation and activity of the osteoclasts. In rheumatoid arthritis (RA), bone erosions are the result of osteoclastic bone resorption at the sites of synovitis, where RANKL expression is also found. Furthermore, magnetic resonance imaging (MRI) bone edema in RA indicates the presence of active inflammation within bone and the presence of osteitis, which is also associated with the expression of RANKL. Bone loss has been documented in the cortical and trabecular bone in the joints of the hand of RA patients. Both synovitis and periarticular bone involvement (osteitis and bone loss) are essential components of RA: they occur early in the disease and both are predictive for the occurrence and progression of bone damage. RANKL knockout mice and mice treated with OPG did not develop focal bone loss, in spite of persistent joint inflammation. Inhibition of osteoclasts by denosumab, a humanized antibody that selectively binds RANKL, has revealed in patients with RA that the occurrence of erosions and periarticular bone loss can be halted, however without affecting synovial inflammation. This disconnect between inflammation and bone destruction opens new ways to separately focus treatment on inflammation and osteoclastogenesis for preventing and/or minimizing the connection between joints and subchondral bone and bone marrow.

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Treatment aims in rheumatoid arthritis

ESC CardioMed ◽

10.1093/med/9780198784906.003.0273 ◽

2018 ◽

pp. 1120-1121

Author(s):

Oliver Distler ◽

Adrian Ciurea

Keyword(s):

Rheumatoid Arthritis ◽

Cardiovascular Disease ◽

Risk Factor ◽

Systemic Inflammation ◽

Independent Risk Factor ◽

Joint Destruction ◽

Joint Inflammation ◽

High Grade

Treatment of rheumatoid arthritis aims at targeting joint inflammation, inhibiting joint destruction, limiting extra-articular involvement, and preventing systemic co-morbidities, the most important being cardiovascular disease. Rheumatoid arthritis has been shown to be an independent risk factor for cardiovascular disease, mostly through high-grade systemic inflammation.

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Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2011-200198 ◽

2011 ◽

Vol 71 (1) ◽

pp. 108-113 ◽

Cited By ~ 41

Author(s):

Maria J H Boumans ◽

Rogier M Thurlings ◽

Lorraine Yeo ◽

Dagmar Scheel-Toellner ◽

Koen Vos ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Joint Destruction ◽

Bone Destruction ◽

Nuclear Factor Κb ◽

Type I ◽

Nuclear Factor ◽

Rankl Expression ◽

Osteoclast Precursors ◽

Receptor Activator ◽

Hands And Feet

ObjectivesTo examine how rituximab may result in the inhibition of joint destruction in rheumatoid arthritis (RA) patients.MethodsTwenty-eight patients with active RA were treated with rituximab. Radiographs of hands and feet before and 1 year after therapy were assessed using the Sharp–van der Heijde score (SHS). Expression of bone destruction markers was evaluated by immunohistochemistry and immunofluorescence of synovial biopsies obtained before and 16 weeks after the initiation of treatment. Serum levels of osteoprotegerin, receptor activator of nuclear factor κB ligand (RANKL), osteocalcin and cross-linked N-telopeptides of type I collagen (NTx) were measured by ELISA before and 16 weeks post-treatment.ResultsAfter 1 year, the mean (SD) change in total SHS was 1.4 (10.0). Sixteen weeks after treatment there was a decrease of 99% in receptor activator of nuclear factor κB-positive osteoclast precursors (p=0.02) and a decrease of 37% (p=0.016) in RANKL expression in the synovium and a trend towards reduced synovial osteoprotegerin expression (25%, p=0.07). In serum, both osteoprotegerin (20%, p=0.001) and RANKL (40%, p<0.0001) levels were significantly reduced 16 weeks after treatment, but the osteoprotegerin/RANKL ratio increased (157%, p=0.006). A trend was found towards an increase of osteocalcin levels (p=0.053), while NTx concentrations did not change.ConclusionsRituximab treatment is associated with a decrease in synovial osteoclast precursors and RANKL expression and an increase in the osteoprotegerin/RANKL ratio in serum. These observations may partly explain the protective effect of rituximab on the progression of joint destruction in RA.

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AB0106 THE SERUM N-ACETYLGLUCOSAMINE CONCENTRATIONS IN RHEUMATOID ARTHRITIS PATIENTS ARE ASSOCIATED WITH JOINT DESTRUCTION AND RELATED METABOLISM MORE THAN INFLAMMATORY CONDITION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3637 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1352.2-1352

Author(s):

S. Tsuboi ◽

T. Matsumoto ◽

Y. Kagawa

Keyword(s):

Rheumatoid Arthritis ◽

Articular Cartilage ◽

Negative Correlation ◽

High Speed ◽

Wrist Joint ◽

Cartilage Damage ◽

Joint Destruction ◽

Basal Metabolism ◽

Joint Disease ◽

Precipitation Method

Background:In rheumatoid arthritis (RA) patients, synovitis causes severe articular cartilage damage. N-acetylglucosamine (NAc-Glc) is a component of gluglucosaminoglycans (GAG) such as hyaluronic acid (HA) and keratan sulfate (KS), heparan sulfate (HS). NAc-Glc concentration in plasma is thought to reflect the balance between biosynthesis and destruction of articular cartilage, however, few studies had examined the relationship between plasma NAc-Glc conncentration and RA activity.Objectives:NAc-Glc concentrations in RA patients were measured, and association with clinical indicators was assessed.Methods:A cross-sectional study was carried out including 60 RA cases. Using N-acetylglucosamine-d3 as standard, the serum of subjects were deproteinized by protein precipitation method with acetonitrile, then concentration of NAc-Glc was measured with high-speed liquid chromatography mass spectrometer (LC-MS / MS). Clinical evaluation items: basic metabolism, presence or absence of exercise habit, Larsen score of knee and wrist joint, therapeutic agents (csDMARDs, biologics and PSL), DAS28, CRP, MMP-3, modified HAQ score (mHAQ). Statically analyzed by Spearman non parametric test.Results:The age of 60 RA cases was 59.7±16.4 years, and the duration of the disease was 10.4±8.7 years. Biologics were used in 29 cases (TNF inhibitors in 16 cases, IL-6 inhibitors in 4 cases, Abatacept in 9 cases), MTX in 32 cases, and prednisolone in 15 cases.Plasma NAc-Glc concentration was 113±41 (ng/dl), DAS28CRP was 3.04±1.2, and mHAQ was 0.863±891. Plasma NAc-Glc concentration showed positive correlation with age (correlation coefficient 0.644), knee joint destruction (0.425), HAQ score (0.340), BUN (0.412), and RF (0.287). Plasma NAc-Glc concentrations also negatively correlated with eGFR (-0.597), MTX use (-0.389), basal metabolism (-0.313), and sex difference (-0.272). There was no correlation between plasma NAc-Glc concentration and body weight, BMI, DAS28, CRP, MMP-3, NTX, serum creatinine, hand joint disease, and transaminase.In this study, plasma NAc-Glc concentration had increased with age, and had have a negative correlation with basal metabolism. Considering these results, it is unlikely that NAc-Glc is released into plasma as a metabolite of synthesis promotion. Further, since NAc-Glc had a negative correlation (-0.389) with MTX as a folic acid inhibitor, it was supposed to be affected by protein synthesis reduction. Because no correlation between NAc-Glc and inflammation or bone metabolism markers was observed, NAc-Glc may represent removal of GAG from the cell membrane (shedding).In previous GAGs studies, in RA patients, HA, KS, CRP, DAS28, was very associated with arthritis, such as MMP-3.The concentration of NAc-Glc in plasma was more relevant to dysfunctions such as destruction and HAQ due to arthritis such as HAQ than inflammatory indicators such as DAS28, MMP-3 and CRP. It is appearing in the plasma by destruction by shedding, as an index to see the joint destruction, it was presumed to be a better indicator than the GAGs. It was also thought that there is a possibility that MTX affects cartilage substrate metabolism.Conclusion:Serum NAc-Glc concentration in rheumatoid arthritis patients may represent cartilage metabolism and joint destruction.References:[1]Y.Matsuura. et al.Ann.Rheum.Dis. 2018;77: 1219-1225[2]T D Spector.et al. Ann.Rheum.Dis. 1992;51: 1134-1137Disclosure of Interests:None declared

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Effects of Mild and Moderate Monoclonal Antibody Dose on Inflammation, Bone Loss, and Activation of the Central Nervous System in a Female Collagen Antibody-induced Arthritis Mouse Model

Journal of Histochemistry & Cytochemistry ◽

10.1369/00221554211033562 ◽

2021 ◽

pp. 002215542110335

Author(s):

Bonnie Williams ◽

Florence Lees ◽

Helen Tsangari ◽

Mark R. Hutchinson ◽

Egon Perilli ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cartilage Damage ◽

Joint Destruction ◽

Joint Damage ◽

Joint Inflammation ◽

Lumbar Spinal Cord ◽

The Central Nervous System ◽

Lumbar Spinal ◽

Glial Reactivity

Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice ( n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV; (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue; and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.

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Cartilage and Bone Biomarkers in Rheumatoid Arthritis: Prediction of 10-year Radiographic Progression

The Journal of Rheumatology ◽

10.3899/jrheum.080180 ◽

2009 ◽

Vol 36 (2) ◽

pp. 266-272 ◽

Cited By ~ 42

Author(s):

SILJE W. SYVERSEN ◽

GURO L. GOLL ◽

DÉSIRÉE van der HEIJDE ◽

ROBERT LANDEWÉ ◽

PER IVAR GAARDER ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Matrix Protein ◽

Radiographic Progression ◽

Joint Destruction ◽

Nuclear Factor Κb ◽

Serum Samples ◽

Human Cartilage ◽

Radiographic Damage ◽

Baseline Serum ◽

And Cartilage

Objective.As current predictors of joint destruction have low specificity, serological biomarkers reflecting bone and cartilage destruction have been proposed as tools in assessing prognosis of rheumatoid arthritis (RA). We examined whether serum concentrations of a panel of biomarkers could predict radiographic progression in patients with RA.Methods.A cohort of 238 patients with RA was followed longitudinally for 10 years with collection of clinical data and serum samples. These analyses focus on the 136 patients with radiographs of the hands available at baseline and at 5 and/or 10 years. Radiographs were scored according to the van der Heijde-modified Sharp score (SHS). Baseline sera were analyzed for receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), human cartilage glycoprotein-39 (YKL-40), C2C, collagen cross-linked C-telopeptide (CTX-I), and cartilage oligomeric matrix protein (COMP). Multivariate linear and logistic regression analyses were used to identify predictors of radiographic progression.Results.Baseline CTX-I levels were higher in progressors [0.41 ng/ml (interquartile range 0.31–0.75)] than in nonprogressors [0.32 ng/ml (IQR 0.21–0.49)], and were independently associated with 10-year change in radiographic damage score [ß = 16.4 (IQR 5.7–27.1)]. We found no association between radiographic progression and baseline serum levels of RANKL, OPG, C2C, YKL-40, or COMP.Conclusion.This longterm followup study of patients with RA indicates a relationship between elevated CTX-I levels in serum and subsequent joint destruction. This association was, however, weak, and our study does not support that serum CTX-I or any of the other tested biomarkers will serve as more useful prognostic markers than current predictors such as anti-cyclic citrullinated peptide, radiographic damage early in the disease course, and signs of inflammation.

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