title: Interleukin-1 induces chondrocyte protease production: the development of collagenase inhibitors.
abstract: Supernatants from the P388D1 macrophage cell line as well as human interleukin-1 (IL-1) stimulated primary rabbit articular chondrocytes to produce collagen- (C-ase) and proteoglycan- (PG-ase) degrading proteases. The P388D1 derived factor had a molecular weight of 16,000-20,000 and a pI of 4.5-5.0. Both protease activities were metal dependent and inhibited by EDTA, phenanthroline, and alpha 2-macroglobulin but not by PMSF, TLCK, pepstatin, or alpha 1-antitrypsin. Size exclusion chromatography indicated the molecular weights for latent PG-ase and C-ase were 44,000-56,000 and 34,000-44,000, respectively. Chemical synthesis efforts produced two classes of C-ase inhibitors--thiols and hydroxamic acids. The former had IC50 values of 10(-5)-10(-6) M while the latter approached 10(-7) M.
authors.affiliation: Stuart Pharmaceuticals, Division of ICI Americans Inc., Wilmington, Delaware.
authors.forename: R D
authors.initials: RD
authors.lastname: Pasternak
authors.forename: S J
authors.initials: SJ
authors.lastname: Hubbs
authors.forename: R G
authors.initials: RG
authors.lastname: Caccese
authors.forename: R L
authors.initials: RL
authors.lastname: Marks
authors.forename: J M
authors.initials: JM
authors.lastname: Conaty
authors.forename: G
authors.initials: G
authors.lastname: DiPasquale
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D010450:Endopeptidases / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D007375:Interleukin-1 / Q000494:pharmacology*; D008666:Metalloendopeptidases; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008970:Molecular Weight; D010447:Peptide Hydrolases / Q000096:biosynthesis*
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D010450:Endopeptidases; D010447:Peptide Hydrolases; C022474:proteoglycan-degrading metalloendopeptidases; D008666:Metalloendopeptidases; D003012:Microbial Collagenase