Modulation by Transforming Growth Factor-β1 and Interleukin-1β of Proteoglycan Release and Chondrodisaccharide Composition in Porcine Articular Cartilage

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Abstract
The effects of IL-1 beta and TGF-beta 1 on proteoglycan release and modifications in porcine articular cartilage explants are described. Proteoglycan release in culture medium was markedly increased when cartilage was treated with IL-1 beta (5 to 100 ng/mL). Addition of IL-1 beta alone or in combination with TGF-beta 1 to cartilage culture stimulated the production and release of PGE2. Indomethacin (10(-6) M) did not modify the IL-1 beta effect on proteoglycan release. Both the spontaneous and IL-1 beta-induced proteoglycan release were downregulated by TGF-beta 1 (50 ng/mL). Basal and stimulated loss of proteoglycans was reduced by the addition of cycloheximide (10(-6) M) and by metalloprotease inhibitors. GAGs of conditioned medium and extracellular matrix proteoglycans were digested to about 90% by chondroitin ABC lyase, suggesting that CS is the major GAG present. Structural analysis of disaccharides, by CZE, revealed a different pattern of oxysulfation when cartilage explants were treated either with IL-1 beta or TGF-beta 1. Indeed, analysis of GAGs, released into the medium from TGF-beta 1-treated cartilage, showed a reduction in the level of 4-S-disaccharide (delta Di4S and an increase in desulfated disaccharides delta Di0S). In the extracellular matrix, IL-1 beta and TGF-beta 1 induced a more complex rearrangement of the GAGs, in that the levels of delta Di0S and delta Di4S were increased whereas those of delta Di6S were decreased. Altogether, these results suggest that TGF-beta 1 does not only counteract the effect of IL-1 beta on proteoglycan release, but modifies the structure of GAGs, probably by interfering with the activity or the synthesis of sulfotranspherases involved in GAG biosynthesis.

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