Rheumatoid behavior in normal human synovial fibroblasts induced by extracts of Gram-negative bacteria.

We have previously shown that exposure of normal human synovial cells to whole extracts of Gram-negative bacteria or purified endotoxins results in increased synthesis of hyaluronic acid, and increased glucose uptake and lactate output. Derivatives of Gram-negative bacteria, therefore, duplicate the major known actions of connective tissue activating peptide (CTAP). The studies presented here demonstrate that, in addition to the hypermetabolic changes, extract-treated synovial cells become hyposensitive to CTAP and acquire accelerated growth rates. Furthermore, the cellular alterations which occur following a short bacterial product-synovial fibroblast interaction period (72 hours) persist for varying lengths of time, in some cases for as long as the cells are followed in culture (up to 38 days). Additional data presented suggest that bacterial products induce CTAP formation or activation within synovial fibroblasts. Pre-incubation of bacterial endotoxin in fresh normal human serum does not alter its ability to activate synovial cells. Many of the cellular alterations induced by bacterial products and endotoxin (derivatives of infectious agents) resemble the abnormal metabolism of rheumatoid synovium in vivo and are characteristic of the behavior of rheumatoid connective tissue fibroblasts grown in vitro. Furthermore, the persistence of the bacterial extract-induced behavior resembles the semi-autonomy of the cultured rheumatoid synovial cell, at least for a limited period of observation.