Disease relevance of Ahsg

• Using the Multiple intestinal neoplasia/+ (Min/+) mouse model of intestinal tumorigenesis, we found twice as many intestinal polyps overall, twice as many large polyps (>3 mm diameter), and more progression to invasive adenocarcinoma in Min/+ Ahsg-/- mice than in littermates expressing Ahsg [1].
• Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene [2].
• Our results suggest that Ahsg may be useful for prevention of the heterotopic ossification and the regulation of osteoinductive effects of BMP used with grafts [3].
• Using reporter gene assays in hepatoma cells combined with electrophoretic mobility shift assays we determined that dexamethasone up-regulates hepatic Ahsg [4].
• Similarly, intrasplenic injection of LLC cells resulted in rapid colonization of the liver with metastasis to the lungs within 2 weeks in the WT but not fetuin-A null mice [5].

High impact information on Ahsg

• This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation [6].
• The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification [6].
• We tested the role of systemic fetuin in tumor cell growth and metastasis by injecting Lewis lung carcinoma (LLC) cells into fetuin-A null and their wild-type (WT) littermate control C57BL/6 mice via the tail vein, s.c., and intrasplenic routes [5].
• The serum glycoprotein fetuin-A promotes Lewis lung carcinoma tumorigenesis via adhesive-dependent and adhesive-independent mechanisms [5].
• However, bone formation was increased in Ahsg(-/-) mice as indicated by greater cortical thickness, accelerated trabecular bone remodeling, and increased osteoblast numbers on bone surfaces [7].

Chemical compound and disease context of Ahsg

• Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg(tm1Mbl)) [2].

Biological context of Ahsg

• The normal age-related increase in cortical thickness and bone mineral density was accelerated in Ahsg(-/-) mice and was associated with increased energy required to fracture [7].
• This may explain the non-linear relationship between ectopic bone formation characteristics and Ahsg(+/+), Ahsg(+/-) and Ahsg(-/-) genotypes, although the increase in satellite bone formation might also explain this phenomenon [3].
• Genomic clones derived from a mouse Svj 129 genomic library were sequenced in order to characterize the intron-exon organization of the mouse Ahsg gene, including an 875 bp subclone containing 154 bp upstream from the transcription start site, the first exon, and part of the first intron [8].
• NH2-terminal amino acid sequence analysis of the intact molecule and three peptides obtained by CNBr digestion revealed that a total of 93 amino acid residues could be aligned with stretches in human alpha 2-HS glycoprotein, bovine fetuin, and rat pp63 (rat fetuin) [9].
• alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling [7].

Anatomical context of Ahsg

• Maturation of growth plate chondrocytes was impaired, and femurs lengthened more slowly between 3 and 18 months of age in Ahsg(-/-) mice [7].
• Here we demonstrate that Ahsg reduces cytokine binding to its cognate receptor in HOS osteocyte cells and suppresses intracellular signaling, while in vivo, we test the hypothesis that Ahsg-deficient mice are hyper-responsive to BMP-induced osteogenesis [3].
• Human alpha 2-HS glycoprotein and bovine fetuin prepared without use of ethanol inhibited trypsin and pancreatic and neutrophil elastases [9].
• Importantly, anti-fetuin-A antibodies inhibited invasion of hepatocytes by sporozoites [10].
• These data demonstrate that the extracellular region of TRAP interacts with fetuin-A on hepatocyte membranes and that this interaction enhances the parasite's ability to invade hepatocytes [10].

Associations of Ahsg with chemical compounds

• A high degree of sequence identity in mouse, rat and human Ahsg promoters suggests that the promoter is similarly up-regulated by dexamethasone in all three species [4].
• A steroid response unit at position -146/-119 within the mouse Ahsg promoter mediates the glucocorticoid-induced increase of Ahsg mRNA [4].
• alpha2-HS glycoprotein (AHSG), also known as fetuin-A, inhibits insulin receptor autophosphorylation and tyrosine kinase activity in vitro and in vivo [11].

Other interactions of Ahsg

• Bone formation in response to implanted BMP cytokine extended further from the implant in Ahsg(-/-) compared with Ahsg(+/+) mice, confirming the interaction between ASHG and TGF-beta/BMP cytokines in vivo [7].

Analytical, diagnostic and therapeutic context of Ahsg

• Using electron microscopy and dynamic light scattering, we demonstrate that precipitation inhibition by Ahsg is caused by the transient formation of soluble, colloidal spheres, containing Ahsg, calcium, and phosphate [12].
• This correlated with a decrease in tumor burden in fetuin-A null animals compared to wild-type weeks 18-22 from tumor onset [13].
• Confocal microscopy and electron microscopy-immunogold demonstrated that fetuin-A was internalized by VSMC and concentrated in intracellular vesicles [14].
• Western blot and immunohistochemistry demonstrated that serum-derived fetuin-A co-localized with calcified human vascular smooth muscle cells (VSMC) in vitro and in calcified arteries in vivo [14].
• Molecular cloning and sequencing of cDNA encoding plasma countertrypin, a member of mammalian fetuin family, from the Mongolian gerbil, Meriones unguiculatus [15].

References