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The role of resident synovial cells in destructive arthritis

https://doi.org/10.1016/j.berh.2008.01.004Get rights and content

Infiltration by inflammatory cells, thickening of the lining layer, and destructive invasion into cartilage and bone are pathognomic features of the synovium in rheumatoid arthritis (RA). However, the most common cell types at the sites of invasion are resident cells of the joint, in particular synovial fibroblasts. These cells differ from healthy synovial fibroblasts in their morphology, their expression of proto-oncogenes and antiapoptotic molecules, and in their lack of certain tumor suppressor genes. Through their production of proinflammatory cytokines and chemokines mediated by signaling via Toll-like receptors, they are not only effector cells but also active parts of the innate immune system attracting inflammatory immune cells to the synovium. Most importantly, by producing matrix-degrading molecules they contribute strongly to the destructive mechanisms operative in RA.

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

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