Morphologic and mitogenic responses of rabbit synovial fibroblasts to transforming growth factor β require transforming growth factor α or epidermal growth factor

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Abstract
We tested the hypothesis that normal synovial fibroblasts might proliferate in response to transforming growth factors (TGFs), peptides that are extracted with acid-ethanol from bovine kidney or salivary gland and that cause anchorage-independent growth of normal cells. A 72-hour exposure of confluent monolayers of rabbit synovial fibroblasts in 10% fetal calf serum to partially purified TGF-β in the presence of TGF-β gave a 2- to 5-fold increase in incorporation of 3H-thymidine, protein content, and cell number. Similar results were obtained with high pressure liquid chromatography-purified TGF-β in the presence of epidermal growth factor (EGF) (a type of TGF-β). By itself, purified TGF-β was not mitogenic; it depended absolutely on EGF. However, only TGF-β along with EGF, and not EGF alone, induced a marked morphologic change: a piling up of cells into foci resembling those commonly seen in primary cultures of rheumatoid synovial cells. Mitogenic responses induced by the TGF-β-EGF combination were prevented by all-trans-retinoic acid but not by indomethacin or dexamethasone. The data indicate that TGF-β, a peptide extracted from normal cells, can act in concert with EGF to cause proliferation and piling up of synovial cells and raise the possibility that these factors may play a role in rheumatoid arthritis and other proliferative but nonmalignant diseases as well.