Bone Morphogenetic Protein-1/Tolloid-related Metalloproteinases Process Osteoglycin and Enhance Its Ability to Regulate Collagen Fibrillogenesis

Abstract

The mammalian bone morphogenetic protein-1 (BMP-1)/Tolloid-related metalloproteinases play key roles in regulating formation of the extracellular matrix (ECM) via biosynthetic processing of various precursor proteins into mature functional enzymes, structural proteins, and proteins involved in initiating the mineralization of hard tissue ECMs. They also have been shown to activate several members of the transforming growth factor-␤ superfamily, and may serve to coordinate such activation with formation of the ECM in morphogenetic events. Osteoglycin (OGN), a small leucine-rich proteoglycan with unclear functions, is found in cornea, bone, and other tissues, and appears to undergo proteolytic processing in vivo. Here we have successfully generated recombinant OGN and have employed it to demonstrate that a pro-form of OGN is processed to varying extents by all four mammalian BMP-1/Tolloid-like proteinases, to generate a 27-kDa species that corresponds to the major form of OGN found in cornea. Moreover, whereas wild-type mouse embryo fibroblasts (MEFs) produce primarily the processed, mature form of OGN, MEFs homozygous null for genes encoding three of the four mammalian BMP-1/Tolloid-related proteinases produce only unprocessed pro-OGN. Thus, all detectable pro-OGN processing activity in MEFs is accounted for by products of these genes. We also demonstrate that both proand mature OGN can regulate type I collagen fibrillogenesis, and that processing of the prodomain by BMP-1 potentiates the ability of OGN to modulate the formation of collagen fibrils.Bone morphogenetic protein-1 (BMP-1) 1 is the prototype of a class of structurally similar metalloproteinases that play various morphogenetic roles in a broad spectrum of species (1, 2).There are four mammalian members of this family: BMP-1, mammalian Tolloid (mTLD), and mammalian Tolloid-like 1 and 2 (mTLL-1 and mTLL-2) (3-5). BMP-1 and mTLD are encoded by alternatively spliced mRNAs of the same gene (3), whereas mTLL-1 and -2 are genetically distinct (4, 5). These proteinases play key roles in regulating formation of mammalian extracellular matrix (ECM), via biosynthetic processing of precursor proteins to form mature, functional matrix components. In the case of collagen fibers, this includes processing of the C-propeptides of procollagens I-III to yield the major fibrous components of ECM (5-9); proteolytic activation of the enzyme lysyl oxidase (10), which is necessary to the formation of covalent cross-links in collagen and elastic fibers (11); and processing of NH 2 -terminal globular domains, or in some cases C-propeptides, of minor fibrillar procollagen V and XI chains (12-14) to yield type V and XI monomers. Such monomers are incorporated into collagen types I and II fibrils, respectively, and appear to control the shapes and diameters of the resultant heterotypic collagen fibrils (15-18). Members of the same small group of proteinases also process precursors for laminin 5 (19, 20) and type VII collagen (21), both of which are involved in securing epithelia...

Immunoproteomic identification of bovine pericardium xenoantigens

“…The identification of the extracellular matrix protein osteoglycin as a putative BP antigen has important implications for the use of BP as a biomaterial. Osteoglycin is a keratin sulphate proteoglycan, involved in collagen fibrillogenesis [60,61]. It has become increasingly clear that the assumption that xenoantigens are likely to be cell-associated is not valid.…”

Shared gene expression profiles in developing heart valves and osteoblast progenitor cells

“…Asporin, also called periodontal ligament-associated protein (PLAP), is a negative regulator of osteoblast mineralization and calcification in periodontal ligament cells (51), and mutations in human Aspn are associated with osteoarthritis (22). Osteoglycin can regulate collagen fibrillogenesis and is dynamically regulated during atherosclerotic progression (11,14). The abilities of these proteins to prevent osteoblast mineralization and affect collagen fibril formation likely contribute to normal valve structure and function.…”

Role of Osteoglycin in the Linkage between Muscle and Bone

“…This interaction between OGN and the TGF-␤ pathway might play some role in the bone anabolic activity by OGN. OGN plays some role in collagen fibrillogenesis in many tissues, such as eye and skin (50,51). OGN is one of the three major keratan sulfate-containing proteoglycans in the cornea, and its glycosaminoglycan side chains seem to affect fibril diameter, interfibrillar spacing, and normal tissue hydration (52).…”