SYNOVIAL CELL ACTIVATION INDUCED BY A POLYPEPTIDE MEDIATOR*

Abstract

Rheumatoid arthritis is exclusively a disease of man, and lack of an experimental animal model has impeded progress in understanding the etiology and pathogenesis of this destructive process. At the level of the synovial membrane, the rheumatoid process is characterized by intermittent connective tissue cell proliferation, overproduction of underpolymerized hyaluronic acid,’ increased glycolysis,2 colonization by various types of inflammatory cells, and abnormalities of the microvasculature.3 In the hope of developing a relevant in vitro investigative model, this laboratory established 61 synovial cell strains from normal individuals and patients with different forms of arthritis. The “abnormalities” detected in the rheumatoid cell strains (TABLE 1) were of particular interest, because these characteristics were propagated from one generation of cells to the Efforts to reproduce the “rheumatoid” characteristics in normal synovial cells by adding rheumatoid sera to the media lead to minor and inconsistent alterations in cellular behavior.‘j Because evidence for humoral factors capable of inducing “rheumatoid behavior” in normal synovial cells was weak, we next examined the response of normal synovial cells to selected cellular factors. Isolated human peripheral blood lymphocytes, polymorphonuclear leukocytes, and platelets were cocultured with monolayer cultures of normal human synovial cells and found to cause profound changes in culture activity. These changes included decreased medium pH, marked acceleration of hyaluronic acid synthesis, and striking increases in glucose uptake and lactic acid formation.’ It soon became clear that slurries of dead leukocytes (frozen-thawed) elicited the same hypermetabolic synovial cell response. Extracts of both syngeneic and allogeneic leukocytes stimulated synovial cells, and because of its protease lability, performance on gel permeation columns, and nondialyzability, the active factor was thought to be a lowmolecular-weight protein.*, Q We termed the constellation of accelerated hyaluronate synthesis, increased glucose uptake, and increased lactate formation connective tissue activation, and the cellular mediator( s) that initiate( s ) this process was named connective tissue activating peptide (CTAP) .9 Major sources and actions of CTAP are summarized in FIGURE 1.