DEGRADATION OF DECORIN BY MATRIX METALLOPROTEINASES - IDENTIFICATION OF THE CLEAVAGE SITES, KINETIC ANALYSES AND TRANSFORMING GROWTH-FACTOR-BETA-1 RELEASE

Decorin (DCN) is a ubiquitous proteoglycan comprised of a core protein attached to a single dermatan/chondroitin sulphate glycosaminoglycan chain. It may play a role in regulation of collagen fibrillogenesis an d function as a reservoir of transforming growth factor beta (TGF-beta ) in the extracellular milieu. We have examined the susceptibility of DCN to five different matrix metalloproteinases (MMPs): MMP-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matr ilysin) and MMP-9 (gelatinase B). MMP-2 and MMP-3 digest DCN into seve n major fragments in a similar pattern. The N-terminal sequence of the two fragments generated by MMP-2 and MMP-3 is Leu(211)-Lys-Gly-Leu-As n, but that of the others is Asp(1)-Glu-Ala-Ser-Gly. MMP-7 cleaves DCN into three major fragments which have the N-termini Asp(1)-Glu-Ala-Se r-Gly, Glu(2)-Ala-Ser-Gly-Ile and Leu(244)-His-Leu-Asp-Asn. Activities of MMP-1 and MMP-9 against DCN are negligible. The values of K-m for the MMPs capable of degrading DCN are very similar (10-12 mu M), but t he k(eat)/K-m value for MMP-7 (30.5 mu M(-1).(-1)) is 4.5-fold higher than those for MMP-2 and MMP-3. Incubation of a DCN-TGF-beta 1 complex with MMP-2, -3 or -7 results in release of TGF-beta 1 from the comple x. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions medi ated by TGF-beta 1 released from DCN in the connective tissues.