Control of extracellular matrix biosynthesis by the bone morphogenetic protein-1/Tolloid-like metalloproteinases

The vertebrate extracellular matrix (ECM) maintains tissue integrity and provides a substratum that contributes to activities such as cellular differentiation and migration during embryonic development and in adult organisms. The major ECM components, collagen types I--III, form aggregates whose turnover is dictated by several classes of proteinases. The process of ECM degradation is well characterized; however the mediators of ECM biosynthesis have only recently begun to be clarified. Identified as inducers of mammalian bone formation and effectors of dorsal-ventral patterning in early Drosophila embryogenesis, the bone morphogenetic protein-1 (BMP-1)/Tolloid-like metalloproteinases were later revealed as key mediators of type I-III collagen biosynthesis. This role is potentiated by the procollagen C-proteinase enhancers, whose functions are to promote BMP-1/Tolloid-like enzymatic activities against procollagen types I--III, a key step in the assembly of fibrillar collagen aggregates.; The biosynthesis of collagen is further influenced by interactions with other macromolecules. Among such molecules, the small leucine-rich proteogycans (SLRP's) affect molecular assembly and physical packing of collagen fibrils. Interestingly, SLRP's are themselves activated by the BMP-1/Tolloid-like enzymes. Additionally, the BMP-1/Tolloidlike proteinases have been shown to activate lysyl oxidase, the enzyme responsible for covalent crosslinking of collagen fibrils in vivo. The quantitatively minor fibrillar collagen types V and XI regulate the assembly of the major collagen fibers. However, although these minor collagens are subject to proteolytic maturation, characterization of these events has been incomplete. Finally, the small integrin binding ligand N-linked glycoproteins (SIBLING's), including dentin matrix protein-1 and dentin sialophosphoprotein, interact directly with and modulate the biomineralization of collagen aggregates in hard tissues such as bone and dentin. However, although SIBLING's are biosynthetically processed in vivo, the responsible proteinases remain to be identified. The previously observed roles for BMP1/Tolloid-like proteinases in the biosynthesis of collagen-associated macromolecules, together with the proteolytic maturation of the minor collagens and SIBLING proteins, suggest that BMP-1/Tolloid-like proteinases may be involved in the biosynthesis of the latter two classes of proteins. The studies herein focus on the proteolytic events that surround collagen biosynthesis, and provide novel insights towards a conceptual model for the molecular activities that foster ECM maturation in vivo.