Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems

Abstract

Microfibril-associated glycoprotein-1 (MAGP-1) is a small molecular weight component of the fibrillin-rich microfibril. Gene-targeted inactivation of MAGP-1 reveals a complex phenotype that includes increased body weight and size due to excess body fat, an altered wound healing response in bone and skin, and a bleeding diathesis. Elastic tissues rich in MAGP-1-containing microfibrils develop normally and show normal function. The penetrance of MAGP-1-null phenotypes is highly variable and mouse strain-dependent, suggesting the influence of modifier genes. MAGP-1 was found to bind active transforming growth factor-␤ (TGF-␤) and BMP-7 with high affinity, suggesting that it may be an important modulator of microfibrilmediated growth factor signaling. Many of the phenotypic traits observed in MAGP-1-deficient mice are consistent with loss of TGF-␤ function and are generally opposite those associated with mutations in fibrillin-1 that result in enhanced TGF-␤ signaling. Increased body size and fat deposition in MAGP-1-mutant animals are particularly intriguing given the localization of obesity traits in humans to the region on chromosome 1 containing the MAGP-1 gene.Microfibrils are important contributors to the structural integrity of tissues and participate in the assembly of elastic fibers during development. They also serve to bind and sequester growth factors in the extracellular matrix (ECM) 3 (1, 2) and can directly signal cells through sequence motifs that interact with integrins and other cell-surface receptors (3-6). The major structural components of these microfibrils are the fibrillins, large glycoproteins rich in calcium binding epidermal growth factor-like domains (7), and the MAGPs, small, cysteine-rich proteins of unknown function. Other proteins can be localized to microfibrils, but it is not clear whether they are integral or associated proteins (8).MAGP-1, a ϳ20-kDa glycoprotein, is synthesized by most matrix-producing cells (9). The N-terminal half of the molecule contains sites for tyrosine sulfation and transglutaminase crosslinking as well as all of the tri-and tetrasaccharide O-linked sugars (10). The first 20 amino acids of the protein are enriched in acidic residues that, together with the sulfotyrosines, create a region of high negative charge capable of binding cationic proteins. The C-terminal half contains all of the molecule's thirteen cysteine residues and encodes a 54-amino acid sequence that defines a matrix-binding domain that targets MAGP-1 to the ECM. MAGP-1 binds to tropoelastin and type VI collagen (11, 12) and interacts with other molecules with defined structural roles in the ECM such as fibrillin-1 and -2 (13, 14), decorin (15), and biglycan (16). It does not, however, bind to the interstitial collagens I, III, or V (12). MAGP-1 also interacts with and facilitates the shedding of Notch1 (17), but there is no evidence for interaction with integrins.MAGP-2 is the other member of the MAGP family and, like MAGP-1, is covalently associated with fibrillin-containing microfibrils (...

Microfibril Structure Masks Fibrillin-2 in Postnatal Tissues

“…The third 8-cysteine domain is just adjacent to the region containing cryptic epitopes recognized by mAbs 60, 72, 139, and 205, so it is possible that MAGP-1 may mask some of these epitopes. Studies similar to the ones performed here, using MAGP-1 null mice (24) and fibrillin-2 antibodies directed specifically toward these cryptic epitopes, could test this possibility.…”

The Extracellular Matrix Protein MAGP1 Is a Key Regulator of Adipose Tissue Remodeling During Obesity

“…In this issue, Craft et al (8) investigate how ECM components mediate metabolic pathways that are associated with obesity and identify MAGP1 as a key regulator. The MAGPs can bind the active form of TGF-b and thereby regulate its activity (4-6), and mice deficient in MAGP1 have a phenotype consistent with increased TGF-b activity (9). MAGP1-deficient mice have also previously been reported to display increased adiposity (9).…”

Involvement of MAGP1 in ^|^beta;-TCP Enhanced Bone Regeneration

“…MAGP1-deficient mice also showed an increased body weight and size due to excess body fat, an altered wound healing response in bone and skin, and a bleeding diathesis 15) . MAGP1 was also found to bind active TGF-β and BMP7 with high affinity 19) , which suggests that it may be an important modulator of microfibril-mediated growth factor …”

“…MAGP1-deficient mice showed increased fat deposition, a woundhealing defect, bleeding diathesis, and a skeletal phenotype characterized by lesions on their lower limbs suggestive of spontaneous bone fracture 15,19) . [20][21][22] .…”

“…The N-terminal half of the protein contains a cluster of acidic and sulfated tyrosine residues that define a binding domain for cationic proteins, such as growth factors like TGF-β and BMPs. In contrast to fibrillin-1, which binds latent forms of the TGF-β family, MAGP1 binds to active TGF-β and BMPs 15) .…”