Fibroblastoid Synoviocytes: Their Intrinsic and Disease-Modified Phenotype as Revealed by a Differential Subtraction Library Approach

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Through their unique and increasingly defined pattern of gene expression, the fibroblastoid intimal synoviocytes appear to be differentiated to perform a series of functions critical to the biologic function of the normal joint, including responsibility for its developmental patterning and the maintenance of its structural integrity. This phenotype also appears to confer the potential for fostering the development and synovial localization of the autoimmune response underlying rheumatoid arthritis, and to participate in joint destruction. The use of synoviocyte lines cultured from either rheumatoid arthritis or osteoarthritis synovia has facilitated progress in the process of gene discovery, although it remains to be determined the extent to which the distinctive phenotype of cells from rheumatoid arthritis reflects persistent modulation by exposure to the inflammatory microenvironment and the extent to which lines from osteoarthritis synovia include large proportions of more conventional fibroblasts from deeper layers of the joint rather than intimal synoviocytes. The possible explanations of the distinctive phenotype include: being intrinsic to the fibroblastoid intimal synoviocyte lineage, persistent modulation by inflammation, or that the over expression phenotype reflects a genetically determined increased expression due to a disease predisposing regulatory polymorphism. Other genes that are identified as equivalently expressed in both lines cultured from either rheumatoid arthritis or osteoarthritis synovia are likely to be related to the more general role of members of the fibroblastoid lineage, or at least those developing in the synovial milieu.

The profile of genes being identified by us and in other laboratories are relevant to novel functions exhibited by this lineage in the normal joint. Fibroblastoid intimal synoviocytes differ from other fibroblastoid lineage cells in that the structure of the intimal lining involves both homotypic cell-cell interactions and heterotypic interactions with monocytes. Genes encoding receptors selectively expressed in synoviocytes are being identified that appear to be involved in these interactions as well as mediating cell-connective tissue matrix interactions. Additional genes are being recognized that appear responsible for the localization and guidance clues that result in the entrance and differentiation of monocytes in the intima, including certain chemokines such as SDF-1. An exaggeration of this mechanism is likely relevant to nonantigen-specific entry of lymphocytes and monocytes into the joint in inflammation. Genes implicated in the patterning of the central nervous system are expressed constitutively at high levels in synoviocytes, perhaps reflecting a role in the development of the joint architecture. A last group of genes is thought to be induced by cellular activation pathways and their expression could relate to the modulation of the synoviocyte by inflammation.