Proposed causes for RA include: (i) genetic preposition; (ii) pathogenetic immuno-inflammatory responses triggered by environmental agents, particularly microbes; (iii) autoimmu-nity directed against components of synovium and cartilage; (iv) dysregulated production of cytokines; (v) recruitment of immuno-inflammatory cells through induction of inflammatory cell adhesion molecules (e.g., E-selectin, ICAM-1, and VCAM-1); and (vi) transformation of synovial cells into autonomously proliferating cells with tissue-infiltrating nature [often referred to as "transformed-like" phenotype (7)]. We have recently clarified the transformed-like nature of rheumatoid synoviocytes by performing gene expression profile analyses of synoviocytes and elucidated cellular genes specifically activated in RA synoviocytes (8,9). When compared with control synoviocytes obtained from healthy individuals (upon injury) or osteoarthritis (OA) patients, we found that both PDGF receptor a and SDF-1, a chemokine, genes are activated in RA synoviocytes without any external stimulus (8). Interestingly, from the gene knockout studies, it was shown that these factors are required for the development of limb joints. Moreover, when synoviocytes were stimulated with physiological concentration of TNFa, a principal proinflam-matory cytokine, cell fate-determining factors, including Notch 1, Notch 4, and Jagged-2, a ligand for Notch proteins were activated only in RA synoviocytes (9). These findings indicate that RA synoviocytes may have reacquired the "revertant" phenotype mimicking the primordial synoviocytes that exhibit hyperproliferation and invasion, at least in a part. It is possible that this peculiar feature is caused by the long-term inflammatory stimulation, through which constitutive activation of particular signaling and transcription pathways lead to the change in "histone code'' proposed by Allis (see Ref. 10 for review) and eventually change the epigenetic behavior of cells.
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