Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: Matrix metalloproteinases-1 and-13 are involved in cartilage collagen breakdown

Retinoic acid (RetA) and interleukin-1 alpha (IL-l) together can induce a r eproducible release of proteoglycan fragments from bovine nasal cartilage i n culture. However, release of collagen fragments with either agent alone i s often variable. In this study over 70% of the total collagen was released from bovine nasal cartilage in culture by day 14 when RetA and IL-l were c ombined. This release was accompanied by the appearance of collagenolytic a ctivity in the culture medium that cleaved collagen specifically at the 1/4 /3/4 position. Tissue inhibitor of metalloproteinases (TIMP) activity was p resent at day 7 but low or absent in media from resorbing tissue at day 14. The breakdown of cartilage collagen could be prevented by the addition of BB-94, a specific metalloproteinase inhibitor. These results suggest that R etA promotes the early release of TIMP from the tissue and that IL-l stimul ates pro-collagenase secretion which, when activated, exceeds the local con centration of TIMP. Th us in the later stages of culture collagen destructi on occurs. Both MMP-1 and MMP-13 were detected and appear to be involved in IL-l + RetA induced bovine cartilage destruction. However, for the first t ime, we also present evidence to suggest that MMP-13 is the predominant col lagenase in this system. I. Cell. Biochem. 79.519-531, 2000. (C) 2000 Wiley -Lisa Inc.