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.

Purified staphylococcal culture medium stimulates neutral metalloprotease secretion from human articular cartilage

“…Addition of IL-1 to articular cartilage induces the degradation of the cartilage matrix and results in the release of proteoglycan and decrease of the synthesis of proteoglycan and glycosaminoglycan (4,16). The effect of IL-1 on human, bovine, and rabbit articular chondrocytes results in the release of hyaluronate binding region (24,27) and an increase in collagenase and neutral proteoglycanase activity (1,24,28). In studies of human IL-1 effects on bovine nasal and articular cartilage (31), addition of the protein synthesis inhibitor cycloheximide blocked IL-1 stimulation of proteoglycan release, whereas the addition of hydrocortisone had little or no effect on PG release (31).…”

Polysulphated glycosaminoglycans modulate transcription of interleukin-1β treated chondrocytes in monolayer culture

“…The contemporary treatment of OA is aimed at slowing disease progression through alteration of pathobiological pathways. Interleukin-1 (IL-1) has been commonly implicated as a key mediator in the progression of OA (18,23,24,40); it inhibits proteoglycan and type-II collagen synthesis (4,8,20) and promotes cartilage matrix degradation (14,21). Specifically, IL-1 'down-regulates' the expression of genes encoding structural matrix molecules, while simultaneously 'up-regulating' the expression of matrix degradative enzymes in vitro (26).…”