Specific biological activities have been attributed to certain ECM proteolytic fragments (Figure 5).5,19,52,104–122 The term matrikines has been proposed for these fragments. This should not be confused with the term matricryptins, which is more accurately applied to ECM protein domains that are unexposed (and therefore inactive) unless the protein is subject to fragmentation-derived conformational changes. For example, C-terminal cleavage of collagens XV and XVIII, generates restin and endostatin, respectively. Both fragments exert anti-angiogenic activity in vivo.119 Other collagen types also generate biologically active fragments, e.g. collagens IV and VI, which are highly expressed in the cardiac ECM2, as reviewed elsewhere.123 The large proteoglycan versican is cleaved by proteases from the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families.124 Versikine is generated by N-terminal cleavage of versican by ADAMTS-1/4, and influences cell proliferation and apoptosis locally.113 Endorepellin, a C-terminal peptide from perlecan exerts anti-angiogenic effects.120 Last, non-structural ECM proteins also release fragments, e.g. the small leucine-rich proteoglycan decorin releases decorunt and other fragments, that exert local regulatory roles over cytokines and growth factors.52,107,117 Recently, we demonstrated that decorin is fragmented in the cardiac ECM. We detected C- and N-terminal non-tryptic cleavage sites on decorin by MS. The resulting cleavage products may regulate growth factor availability.52 Using similar approaches, the Lindsey group identified cleavage products derived from collagen I that promote scar formation after MI.5 Figure 5Biological activity of ECM fragments. Fragments derived from a variety of ECM proteins (i.e. matrikines) exert functions that regulate diverse cellular and tissue processes. Proteomics offers a tool for the analysis of known ECM fragments as well as the discovery of previously unknown fragments with functions potentially important for cardiac physiology and putative therapeutic targets. *Indicates putative fragments with activities only characterised after exogenous administration. CO1A1, collagen alpha-1(I) chain; FINC, fibronectin; EDA, extra domain A; TENA, tenascin; FN3, fibronectin type III domain; CO6A3, collagen alpha-3(VI) chain; ELN, elastin; PGS2, decorin; CO4A1, collagen alpha-1(IV) chain; OSTP, osteopontin; LAM332, laminin 332; VTNC, vitronectin; CSPG2, versican; EGF, epidermal growth factor-like domain; HGF, hepatocyte growth factor; COIA1, collagen alpha-1(XVIII) chain; PGBM, perlecan; COFA1, collagen alpha-1(XV) chain; POST, periostin; FAS1, fasciclin-like domain; PGCA, aggrecan; HPLN1, hyaluronan and proteoglycan link protein 1.