Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2

We have recently shown that the adhesive defect observed in dermal fibrobla sts derived from thrombospondin 2 (TSP2)-null mice results from an increase in matrix metalloproteinase 2 (MMP2) levels (Yang, Z., Kyriakides, T. R., and Bornstein, P. (2000) Mol. Biol. Cell 11, 3353-3364). Adhesion was resto red by replacement of TSP2 and by inhibitors of MMP2 activity. In pursuing the observation that TSP2 and MMP2 interact, we now demonstrate that this i nteraction is required for optimal clearance of extracellular MMP2 by fibro blasts. Since TSP2 is known to be endocytosed by the scavenger receptor, lo w density lipoprotein receptor-related protein (LRP), we determined whether interference with LRP function affected fibroblast adhesion and/or extrace llular MMP2 levels. Addition of heparin, which competes for the binding of TSP2 to LRP coreceptor proteoglycans, inhibited adhesion of control but not TSP2-null cells, and a blocking antibody to LRP as well as the LRP inhibit or, receptor-associated protein, also inhibited adhesion and increased MMP2 levels only in control fibroblasts. TSP2 did not inhibit active MMP2 direc tly and did not inhibit the activation of pro-MMP2. Finally, the internaliz ation of I-125-MMP2 was reduced in TSP2-null compared with control fibrobla sts. We propose that clearance of MMP2-TSP2 complexes by LRP is an importan t mechanism for the regulation of extracellular MMP2 levels in fibroblasts, and perhaps in other cells. Thus, some features of the phenotype of TSP2-n ull mice, such as abnormal collagen fibrillogenesis, accelerated wound heal ing, and increased angiogenesis, could result in part from increased MMP2 a ctivity.