3The role of resident synovial cells in destructive arthritis
Introduction
The main characteristics of rheumatoid arthritis (RA) are chronic inflammation and progressive joint destruction. The synovial lining layer is thickened and hyperplastic, and synovial villi form. The sublining layer contains proliferating blood vessels and is invaded by inflammatory cells such as lymphocytes, plasma cells, and macrophages. Notably, these migratory inflammatory cells are not usually found at the site of destruction, where the synovium invades into cartilage and bone. Instead, cells that are normally resident in the joint (i.e. fibroblast-like synoviocytes and macrophage-like synoviocytes) are found here (Figure 1a). In this regard, cadherin 11 has not only been identified as an essential factor in the formation of a normally organized synovial lining, but also seems to play a crucial role in the pathological changes observed in RA when the synovium invades cartilage and bone; cadherin-11-null mice show a measurable resistance to the induction of arthritis.1
The inflammatory process in RA is mediated by a multitude of cytokines connected via intricate networks. The success of tumor necrosis factor (TNF)-blocking agents in the treatment of RA provides evidence for a key role of TNFα in the regulation of the inflammatory response. However, about one-third of all patients treated with TNF-blocking agents fail to achieve the response criteria as defined by the American College of Rheumatology.2, 3 There is evidence that insufficient treatment response is associated with low baseline levels of TNF, indicating that different pathogenic pathways might be activated in these patients. Furthermore, the lack of sustained benefit after the termination of anti-TNF therapies suggests an inflammatory-independent mechanism driving chronic inflammation and also joint destruction in RA. Additionally, the hypothesis that matrix-degrading mechanisms are at least partly independent of the inflammatory environment in RA is supported by the recent finding that in a subgroup of patients considered to have reached clinical remission based on a Disease Activity Score lower than 1.6, joint damage continues to worsen.4
In recent years it has become clear that resident synovial fibroblasts are not just innocent bystander cells in the pathological processes of RA, but actively impel joint inflammation and destruction. This chapter highlights the unique phenotype of synovial fibroblasts in RA (RASF) and summarizes the role of RASF in joint destruction and inflammation.
Section snippets
the role of resident synovial cells in destructive arthritis – Inflammation-independent activation
In the 1970s, Fassbender observed that aggressive resident synovial cells invade and destroy cartilage and bone in the joints of patients with RA. The invading cells were described as cytoplasm rich, with large pale nuclei and prominent nucleoli; they were characterized as ‘mesenchymoid transformed’.*5, 6 Further studies showing that the growth of cultured synoviocytes can be anchorage independent and lack contact inhibition supported the concept that a tumor-like tissue might be formed in RA.7
RASF and joint destruction
In the inflamed synovium, RASF are additionally stimulated by a variety of proinflammatory cytokines produced by migratory inflammatory cells.47 Furthermore, special environmental conditions in the joints of patients with RA, such as high pressure and hypoxic conditions due to vascular changes, in combination with increased metabolism, induce gene expression in RASF.48, 49 Microparticles provide a recently discovered means by which RASF can be further stimulated to produce proinflammatory and
Outlook
Over the past years, valuable progression has been made in the elucidation of pathogenetic mechanisms in RA. The development and approval of biological drugs like therapeutics targeting TNFα or the CD20 surface molecule on B cells not only improved the therapeutic options for clinicians and the quality of life for patients but also provided new insights in the mechanisms of the disease.98 However, the etiology of RA remains unknown; not all patients respond satisfactorily to treatment and the
References (103)
Histomorphological basis of articular cartilage destruction in rheumatoid arthritis
Collagen and Related Research
(1983)- et al.
Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis
American Journal of Pathology
(2003) - et al.
Cytoskeletal changes in cell transformation and tumorigenesis
Current Opinion in Genetics and Development
(2001) - et al.
Expression of the collagenolytic and Ras-induced cysteine proteinase cathepsin L and proliferation-associated oncogenes in synovial cells of MRL/I mice and patients with rheumatoid arthritis
Matrix
(1990) - et al.
Expression of Fas antigen and Fas ligand in the rheumatoid synovial tissue
Clinical Immunology and Immunopathology
(1996) - et al.
Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium
American Journal of Pathology
(2003) - et al.
mRNA is an endogenous ligand for Toll-like receptor 3
The Journal of Biological Chemistry
(2004) Chemokine inhibition in inflammatory arthritis
Best Practice and Research. Clinical Rheumatology
(2006)- et al.
Expression of the cytokine RANTES in human rheumatoid synovial fibroblasts. Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines
The Journal of Biological Chemistry
(1993) - et al.
Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts
Immunology Letters
(2007)
Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation
Immunology Letters
Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation
American Journal of Pathology
Repression of protein synthesis by miRNAs: how many mechanisms?
Trends in Cell Biology
Cadherin-11 in synovial lining formation and pathology in arthritis
Science
Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group
The New England Journal of Medicine
Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate
Arthritis and Rheumatism
Radiological damage in patients with rheumatoid arthritis on sustained remission
Annals of the Rheumatic Diseases
What destroys the joint in rheumatoid arthritis?
Archives of Orthopaedic and Trauma Surgery
Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids
The Journal of Clinical Investigation
Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction?
Annals of the Rheumatic Diseases
Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice
American Journal of Pathology
Functional characterization of adherent synovial fluid cells in rheumatoid arthritis: destructive potential in vitro and in vivo
Arthritis and Rheumatism
Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10
Annals of the Rheumatic Diseases
Cytoskeletal rearrangements in synovial fibroblasts as a novel pathophysiological determinant of modeled rheumatoid arthritis
PLoS Genetics
Cooperation of Ras- and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis
Arthritis and Rheumatism
Synovial fibroblast-like cells strongly express jun-B and C-fos proto-oncogenes in rheumatoid- and osteoarthritis
Scandinavian Journal of Rheumatology Supplement
Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric matrix protein
Annals of the Rheumatic Diseases
Apoptosis in rheumatoid arthritis
Current Opinion in Rheumatology
Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability
Journal of Immunology
Bcl-x(L) expression in vivo in rheumatoid synovium
Clinical Rheumatology
HIF-1alpha has an anti-apoptotic effect in human airway epithelium that is mediated via Mcl-1 gene expression
Journal of Cellular Biochemistry
Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl-2
Journal of Immunology
Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis
Arthritis and Rheumatism
Apoptosis in rheumatoid arthritis synovium
The Journal of Clinical Investigation
Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes
Arthritis and Rheumatism
Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis
Annals of the Rheumatic Diseases
Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts
Proceedings of the National Academy of Sciences of the United States of America
Down-regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas-mediated apoptosis
Arthritis and Rheumatism
Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis
Arthritis and Rheumatism
FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis
Arthritis and Rheumatism
Inhibition of death receptor signals by cellular FLIP
Nature
Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy
Genes and Development
Overexpression of synoviolin in peripheral blood and synoviocytes from rheumatoid arthritis patients and continued elevation in nonresponders to infliximab treatment
Arthritis and Rheumatism
Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium
American Journal of Pathology
p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion
Annals of the Rheumatic Diseases
Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium
Proceedings of the National Academy of Sciences of the United States of America
Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene
American Journal of Pathology
PUMA regulation and proapoptotic effects in fibroblast-like synoviocytes
Arthritis and Rheumatism
Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion
Arthritis and Rheumatism
IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in synovial fibroblasts
Journal of Immunology
Cited by (75)
8-Shogaol inhibits rheumatoid arthritis through targeting TAK1
2022, Pharmacological ResearchCitation Excerpt :In RA, however, FLS are epigenetically transformed to actively produce inflammatory cytokines and proteases, directly mediating tissue damage and cellular infiltration [2,7,9]. Clinical and animal studies show that FLS are activated at the early phase of RA development which can precede the onset of clinical symptoms [5,10–13]. The aggressiveness and expansion of FLS appears to correlate with disease progression, immune cell infiltration, and joint damage [2,5,7].
Role of glucose metabolism in aggressive phenotype of fibroblast-like synoviocytes: Latest evidence and therapeutic approaches in rheumatoid arthritis
2020, International ImmunopharmacologyThe role of protein SUMOylation in rheumatoid arthritis
2019, Journal of AutoimmunityCitation Excerpt :These cells have been characterized as having a unique morphology, aberrant expression of anti-apoptotic molecules, proto-oncogenes, and a lack of tumor suppressor gene expression and interaction with endothelial cells, lymphocytes, and macrophages that ultimately results in tissue-specific responses. Additionally, they have been shown to possess a feature characteristic of tumor cells, because they switch inflammation from acute-to-chronic by ‘stable activation’ [42–47]. Evidence has shown that fibroblast-like synoviocytes (FLSs) are major participants in the pathogenesis of RA and is found frequently in the synovium of RA patients.
The proteoglycan biglycan mediates inflammatory response by activating TLR-4 in human chondrocytes: Inhibition by specific siRNA and high polymerized Hyaluronan
2018, Archives of Biochemistry and BiophysicsCitation Excerpt :A prosecution of these studies demonstrated that soluble BGN regulated the balance in IL-1β production in vitro and in vivo by modulating expression activity and stability of NOX enzymes via different TLR-pathways [20]. It is well known that degeneration of joint cartilage is a key feature of arthritis, but the disease is also associated with concomitant changes in the Synovium and Subchondral bone metabolism, causing inflammation of the synovial membrane in the affected joint [21]. There are no effective long-term treatments to counteract arthritis and current research is focused on understanding how the imbalance between specific ECM molecules may influence the progression of the disease.
Epigenetic alterations in chronic disease focusing on Behçet's disease: Review
2017, Biomedicine and PharmacotherapyCitation Excerpt :TLR1 is expressed in leukocyte surface and in other cells, such as astrocytes, fibroblasts, keratinocytes, endothelial, and epithelial cells [56]. It was detected as being expressed also by synovial fibroblasts, including RASF [57]. Recent investigations have revealed that RASF have reduced levels of total DNA methylation, [58] which lead to an improved expression of cell-activating genes and might excite the innate immune response via TLR9.
CD200<sup>+</sup> fibroblasts form a pro-resolving mesenchymal network in arthritis
2024, Nature Immunology