title: Chondrocyte activation by interleukin-1: analysis of the synergistic properties of fibroblast growth factor and phorbol myristate acetate.
abstract: Following activation, monolayers of lapine articular chondrocytes secreted into their culture media large amounts of prostaglandin E2 (PGE2) and the neutral metalloproteinases collagenase and gelatinase. Partially purified preparations of synovial "chondrocyte activating factors" (CAF), which contain interleukin-1 (IL-1), generally proved stronger activators of chondrocytes than recombinant, human, IL-1 alpha (rHIL-1 alpha) or IL-1 beta (rHIL-1 beta). The presence of synergistic cytokines within the synovial material provides one possible explanation of this discrepancy. As first reported by K. Phadke (1987, Biochem. Biophys. Res. Commun. 142, 448-453) fibroblast growth factor (FGF) synergized with rHIL-1 in promoting the synthesis of neutral metalloproteinases. In our hands FGF alone did not induce neutral metalloproteinases and increased PGE2 synthesis only modestly. However, at doses from 1 ng/ml to 1 microgram/ml, FGF progressively enhanced the synthesis of PGE2, collagenase, and gelatinase by chondrocytes responding to rHIL-1. Acidic and basic FGF synergized equally well with both rHIL-1 alpha and rHIL-1 beta. Phorbol myristate acetate (PMA), but not the Ca2+-ionophore A23187, could substitute for FGF as a synergist. PMA alone was a poor inducer of collagenase or gelatinase but, unlike FGF, it greatly enhanced the synthesis of PGE2 by chondrocytes. Dot-blot analyses with a cDNA probe to collagenase mRNA confirmed that partially purified synovial CAF induced collagenase mRNA more effectively than rHIL-1, with rHIL-1 alpha being superior to rHIL-1 beta in this regard. The synergistic effects of both FGF and PMA upon IL-1-mediated collagenase induction were associated with increased abundance of collagenase mRNA.
authors.affiliation: Ferguson Laboratory for Orthopaedic Research, University of Pittsburgh School of Medicine, Pennsylvania 15261.
authors.forename: G
authors.initials: G
authors.lastname: Bandara
authors.forename: C W
authors.initials: CW
authors.lastname: Lin
authors.forename: H I
authors.initials: HI
authors.lastname: Georgescu
authors.forename: D
authors.initials: D
authors.lastname: Mendelow
authors.forename: C H
authors.initials: CH
authors.lastname: Evans
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002358:Cartilage, Articular / Q000201:enzymology / Q000378:metabolism*; D015342:DNA Probes; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D018093:Gelatinases; D007375:Interleukin-1 / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000096:biosynthesis; D003012:Microbial Collagenase / Q000096:biosynthesis; D010434:Pepsin A / Q000096:biosynthesis; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D015342:DNA Probes; D007375:Interleukin-1; D000001:Calcimycin; D005346:Fibroblast Growth Factors; D010434:Pepsin A; D018093:Gelatinases; D008666:Metalloendopeptidases; D003012:Microbial Collagenase; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate