PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE ROLE OF SYNOVIOCYTES

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Rheumatoid arthritis (RA) is traditionally considered to be a T-cell–mediated disease. Additional data have implicated T-cell–independent pathways in its pathogenesis, however, especially in late stages of the disease.26, 32 No one can reasonably dispute that RA is a disease involving immunologic processes34, 84; however, the specific contribution of T cells as initiators or perpetuators of the disease remains difficult to prove. Non–T-cell elements, including macrophage- and fibroblast-like synoviocytes (FLS), are capable of producing cytokines and matrix-degrading enzymes in the joint, proliferating, and invading adjacent tissues, perhaps in an autonomous fashion. These non–T-cell participants could play an essential role in destructive aspects of the disease. In this article, we mainly focus on FLS among these constituents of RA synovial tissues and discuss the characteristics of these cells in relation to transformation, signal transduction, and production of enzymes responsible for joint destruction.

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PARTIAL TRANSFORMATION OF RHEUMATOID ARTHRITIS SYNOVIAL TISSUES OR CELLS

Rheumatoid synovium is characterized by excessive growth and invasion into adjacent tissues, including bone and cartilage.42 In many ways, it behaves and appears like a locally invasive tumor in the joints. In fact, RA synovial tissues or cells exhibit many features of transformation in vivo and in vitro (Table 1). It is unclear, however, whether these cells are permanently changed in association with genetic alterations or are passively responding to the local environment.26

SIGNAL TRANSDUCTION AND TRANSCRIPTION FACTORS IN RHEUMATOID ARTHRITIS

Regulation of cell activation and differentiation is tightly associated with transcription factors that bind DNA and regulate gene transcription. RA reveals marked synovial tissue hyperplasia associated with inflammation, and there is increasing evidence that a number of transcription factor families are involved in these processes.28 Activator protein-1 (AP-1), mitogen-activated protein kinase (MAPK), and nuclear factor κB (NF-κB) are thought to be especially important and have been

MATRIX-MODIFYING ENZYMES: MATRIX METALLOPROTEINASES, AGGRECANASE, AND CYSTEINE PROTEASES

RA is a destructive inflammatory disease in which joint deformity and disability result from extracellular matrix degradation. MMPs, ADAMTS (a disintegration and metalloproteinase with thrombospondin motifs), family members and cysteine proteases are considered to be the primary proteolytic enzymes responsible for degradation of extracellular matrix such as collagen and proteoglycan, for remodeling of connective tissues, and for resulting joint destruction.

SUMMARY

Considering the characteristics of RA synovial tissues such as marked proliferation and invasion to adjacent tissues, comparisons with transformed or neoplastic tissue are natural. RA synovial tissues or cells are not truly malignant, but they have many features of transformation, denoted as “partial transformation” in this article. These features include anchorage-independent growth, loss of contact inhibition, oncogene activation, monoclonal or oligoclonal expansion, detectable telomerase

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    Address reprint requests to Gary S. Firestein, MD, Division of Rheumatology, Allergy, and Immunology, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093–0656

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    Division of Rheumatology, Allergy, and Immunology, School of Medicine, University of California San Diego, La Jolla, California

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