Invasive fibroblast‐like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors?

Abstract

Among the panoply of cells in the rheumatoid synovium, increasing attention has been directed toward non-T cell elements as potential therapeutic targets. While the precise role of T cells as initiators or perpetuators of rheumatoid arthritis (RA) is difficult to quantify, there is little disagreement that macrophages and fibroblasts play an essential part in the destructive aspects and cytokine networks of the disease. This review is designed to examine the biology of the synovial intimal fibroblast in RA and how it participates in this process. Moreover, understanding its role in the pathogenesis of RA offers a variety of novel approaches to controlling both the inflammatory and destructive aspects of arthritis. Type B synoviocytes in the intimal liningThe synovial intimal lining is the interface between the synovium and the intraarticular space. It lacks blood vessels, receiving nutrition and oxygen via a sublining vascular network (1). The lining is normally 1 or 2 layers deep and is supported by a relatively disorganized accumulation of matrix proteins rather than a true basement membrane. Lining cells do not form tight junctions with each other, but instead, are a loosely associated collection of macrophage-like type A synoviocytes and fibroblast-like type B synoviocytes. The former account for the majority of cells in both normal intima and hyperplastic RA tissue; they are derived from monocyte precursors in the bone marrow (2). Type B Gary S . Firestein, MD, Division of Rheurnatology, University of California at San Diego School of Medicine.Address reprint requests to Gary S. Firestein, MD, Division of Rheumatology, University of California at San Diego School of Medicine, #0656, 9500 Gilman Drive, La Jolla, CA 92093.Submitted for publication February 20, 1996; accepted in revised form May 15, 1996. cells have the morphologic appearance of fibroblasts as well as the structural machinery to synthesize and secrete an impressive array of products, including proteoglycans, cytokines, arachidonic acid metabolites, and metalloproteinases.The fibroblast-like synoviocytes (FLS) (3)(4)(5). These proteins are also expressed by fibroblasts in the sublining region. However, some cytoplasmic and cell surface markers distinguish intimal lining FLS from sublining fibroblasts as well as from mesenchymal cells in other tissues.Perhaps the 2 best-defined differences are surface expression of the adhesion molecule VCAM-1 and intracellular localization of the enzyme undine diphosphoglucose dehydrogenase (UDPGD) (6). Prominent VCAM-1 display in the intimal lining of both normal and RA synovial tissue was first observed in frozen sections by immunohistochemistry (7,8) and later, by in situ hybridization (9). Subsequently, VCAM-1 was noted to be expressed constitutively by cultured FLS (7,lO). Sublining fibroblasts and fibroblasts from most other sources, such as skin, do not express VCAM-1. The second distinctive characteristic of FLS, i.e., the expression of UDPGD, confers the ability to synthesize hyaluronan (6). This...

Secretion of pro‐inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast‐like synoviocytes in juvenile idiopathic arthritis

“…Although there are similarities, rheumatoid arthritis (RA) and JIA are distinct entities 3. The pivotal role of the synovial fibroblast‐like synoviocytes (FLS) in RA has been elegantly investigated 4. RA FLS are known to be major contributors to cartilage destruction through release of matrix metalloprotease 3 (MMP3), with relative decreased expression of tissue inhibitors of metalloproteases (TIMPs).…”

“…These aggressive cells are thought to be partially transformed. They display loss of contact inhibition and are able to proliferate in an anchorage‐independent manner, express several oncogenes, and exhibit loss of apoptosis with an increase in pro‐survival signal NF‐κB 4, 6. Although RA and JIA are both destructive arthropathies and display Th1 cytokine profiles, they are clinically quite different diseases.…”

Cyclooxygenase 2–derived prostaglandin E2 production by corticotropin‐releasing hormone contributes to the activated cAMP response element binding protein content in rheumatoid arthritis synovial tissue

“…Pannus is comprised primarily of activated fibroblast-like synoviocytes and macrophages, which penetrate and degrade cartilage and subchondral bone, ultimately leading to joint destruction (1). Activated synoviocytes demonstrate increased cell adhesion molecule expression and increased proliferative and invasive activity, and they release proteolytic enzymes, cytokines, and prostaglandins leading to cartilage erosion (3).…”

Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium

“…One of the hallmarks of RA is the activation of the cells that make up the synovial lining of affected joints. [1][2][3] During RA, the normally thin synovial lining becomes dramatically thickened and hyperplastic due to persistent secretion of inflammatory cytokines such as IL-1 and TNF-a by macrophages and synoviocytes. [4][5][6][7] The expanded synovium becomes aggressive and gradually invades and erodes the articular cartilage and bone, eventually resulting in loss of joint function.…”

“…In many respects the phenotype of the RA synovium is similar to that of an aggressive tumor. 1,8 An analysis of tissue from RA patients suggests that a disruption in the control of the cell cycle or apoptotic pathways may be the cause of the abnormal expansion of cells observed in the rheumatoid synovium. 9,10 This raises the possibility that the delivery of molecules that induce apoptosis to diseased joints may result in a retardation or regression of the aggressive synovium.…”