The synovial lining micromass system: Toward rheumatoid arthritis in a dish?

Abstract

A characteristic feature of rheumatoid arthritis (RA) is the hyperplasia of the synovial lining. In RA, the synovial tissue undergoes a marked transformation, due to the influx of immune cells including monocytes, lymphocytes, mast cells, neutrophils, as well as increased angiogenesis, and synovial fibroblast hyperpasia, resulting in the destruction of cartilage and bone. The synovial lining, which consists of synovial fibroblasts and macrophages derived from circulating monocytes, is attached at the bone-cartilage junction and is the site at which joint damage in RA begins. In normal individuals the synovial lining is 1–3 cell layers thick, but increases to as much as 13 cell layers in patients with RA. The hyperplasia of the synovial lining is a result of an increased number of synovial fibroblasts and macrophages, which occurs due to enhanced proliferation, recruitment, and/or survival. The normal function of synovial fibroblasts is to produce extracellular matrix and contribute to the lubrication of joint by secreting molecules such as hyaluronan and lubricin. Recently, a three dimensional synovial lining type membrane was generated in culture using synovial fibroblasts and matrigel and this lining behaved similar to a normal synovial tissue (1,2). In the current issue of Arthritis & Rheumatism Kiener et al (3) furthered these studies by demonstrating that synovial fibroblasts uniquely orchestrate the incorporation of monocytes into the cultured synovial lining. The mechanisms by which synovial fibroblasts contribute to the pathogenesis of RA have been the focus of studies for many years. Synovial fibroblasts from patients with RA have been shown to display anchorage independence, enhanced invasiveness into cartilage, increased proliferation, and decreased cell death as compared to synovial fibroblasts from patients with osteoarthritis or disease free controls. Further, RA synovial fibroblasts spontaneously secrete numerous cytokines, chemokines, and matrix-metalloproteinases (MMPs) that promote inflammation and joint destruction through autocrine and paracrine mechanisms (4). Thus, the RA synovial fibroblasts do not appear to be innocent bystanders in the pathogenesis of RA, but rather active and crucial participants. Despite these insights, the techniques employed to characterize the mechanisms by which synovial fibroblasts contribute to the pathogenesis of disease may not always reveal the whole story accurately (5). In vitro cell culture employing synovial fibroblasts adherent to plastic culture dishes following 3 or more passages, is the most commonly used approach. This system relies on examining a spontaneous or induced function, such as expression of a cytokine, transcription factor, survival factor or proliferation by RA synovial fibroblasts. While the ease and accessibility of this system is appealing for researchers to conduct their studies, it has become clear that the behavior of synovial fibroblasts may change once they were placed on “plastic” compared with the in vivo observations made by the direct examination of synovial tissue (6). For example, spontaneous differences between RA and control synovial fibroblasts