Disease relevance of Mgp

• While osteocalcin-deficient mice have increased bone formation, MGP-deficient mice have abnormal calcification leading to osteopenia, fractures, and premature death owing to arterial calcification [1].
• These findings suggest that abnormal expression of MGP plays a major role in the pathologic calcification of the twy mouse [2].
• Hypertrophy of abnormally proliferated chondrocyte-like cells, which are different from fibrocartilaginous cells of the annulus fibrosus, was observed in the intervertebral disks of the twy mouse at 3 weeks of age, and MGP gene expression was noted at the same time [2].
• In contrast to the significant difference in the effects of metabolic and respiratory acidosis on bone calcium efflux and osteoblastic collagen synthesis, these two forms of acidosis have a similar effect on osteoblastic RNA expression of both matrix Gla protein and osteopontin [3].
• Furthermore, since MGP-treated athymic mice were also protected against Listeria infection, mature T cells were most likely not involved in this enhanced resistance [4].

High impact information on Mgp

• Mgp-deficient mice additionally exhibit inappropriate calcification of various cartilages, including the growth plate, which eventually leads to short stature, osteopenia and fractures [5].
• Mice that lack Mgp develop to term but die within two months as a result of arterial calcification which leads to blood-vessel rupture [5].
• Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo [6].
• The gene for matrix Gla protein seems to be a specific target of Fra-1 since its expression was markedly increased in the long bones of fra-1-transgenic mice [7].
• Here, we show that restoration of Mgp expression in arteries rescues the arterial mineralization phenotype of Mgp-/- mice, whereas its expression in osteoblasts prevents bone mineralization [8].

Biological context of Mgp

• Matrix Gla protein (MGP) is a potent inhibitor of soft tissue calcification, and Mgp gene deletion in mice results in arterial calcification [9].
• During mouse development, MGP gene expression is detectable as early as day 10.5 of embryonic development (E10.5), before any skeletal structures are identifiable [10].
• This finding raises the intriguing possibility that MGP may play distinct roles during embryogenesis and in the adult organism [10].
• DNA transfection experiments indicate that the mouse MGP promoter functions better in cells expressing the MGP gene than in cells that do not express the gene [10].
• The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development [10].

Anatomical context of Mgp

• Consistent with this observation, TG2 expression and gamma-glutamyl-epsilon-lysyl crosslink levels were also increased in Mgp(-/-) aortas [9].
• In growth plate cartilage, MGP mRNA is present in resting, proliferative, and late hypertrophic chondrocytes [10].
• Surprisingly, MGP mRNA is absent from the early hypertrophic chondrocytes and from the osteoblasts [10].
• This study demonstrates that during development MGP gene expression occurs early and is predominant at the epithelial mesenchymal interfaces, principally of lung and limb buds, and in cells of the chondrocytic lineage [10].
• Finally, the MGP gene is expressed at a lower level in kidney medulla and uterus smooth muscle but not in brain, spleen, or heart during development [10].

Associations of Mgp with chemical compounds

• Here, we examined the mRNA expressions of OPN, MGP, ON, and OC in the kidneys of stone-forming model rats administered an oxalate precursor, ethylene glycol (EG) for up to 28 days [11].
• cDNA and deduced amino acid sequence of mouse matrix gla protein: one of five glutamic acid residues potentially modified to gla is not conserved in the mouse sequence [12].
• However, there are five glutamic acid residues potentially modified to gamma-carboxyglutamic acid (gla) in those species; in murine MGP, lysine replaced glutamic acid 37 [12].
• A cDNA library was constructed using the mouse osteoblastic cell line MC3T3-E1 treated with 1 alpha,25-dihydroxyvitamin D3, based on the finding that the treatment increased ninefold the expression of 0.7 kb matrix gla protein (MGP) mRNA. cDNA clones encoding mouse MGP were isolated from the library [12].
• In contrast, a single injection of PTH increased matrix gamma-carboxyglutamic acid protein (MGP) mRNA in 2-week-old ossicles [13].

Other interactions of Mgp

• Moreover, these mice died significantly earlier (4.4 +/- 0.2 wk) than MGP(-/-) OPN(+/+) counterparts (6.6 +/- 1.0 wk) [6].
• Mild degeneration and abnormal growth of the cartilage in contact with the joint capsule was observed at 5 weeks in the articular cartilage of the ankle joint of the twy mouse, and MGP gene expression was observed at the same time [2].
• Using histology, von Kossa staining, immunohistochemistry, and Western blotting, together with examination of cellular markers for VSMCs and extracellular matrix markers for cartilage, we provide evidence for cell transformation from VSMC to chondrocyte in the arterial media in the absence of Mgp [14].
• At 2 weeks of age in the aorta of Mgp-/- mice, VSMCs lose immunostaining for smooth muscle alpha-actin concomitant with the appearance of cartilage molecules as shown by immunohistochemical staining and Western blotting for aggrecan, link protein, and type II collagen [14].
• OP-1 is strongly mitogenic for ATDC5, showing dose-dependent (2.5-80 ng/ml) induction of Alcian blue staining, alkaline phosphatase activity, and mRNA expression for collagen types II and IX, and matrix Gla protein [15].

Analytical, diagnostic and therapeutic context of Mgp

• Western blot analysis of extracted Mgp(-/-) aortas revealed that the majority of the OPN was in high molecular mass protein complexes, indicating modification by a crosslinking enzyme [9].
• Using immunohistochemistry and light and electron microscopy, we report that following mineralization occurring in the arterial media of Mgp(-/-) aortas, OPN is upregulated and accumulates at the surface of the calcified elastic lamellae [9].
• In situ hybridization analysis shows that MGP mRNA is initially present at the mesenchymal epithelial interphase in lung and limb buds [10].
• The Northern blotting showed that the mRNA expressions of OPN and MGP were markedly increased with the administration of EG, but their expression patterns differed [11].
• Molecular cloning of the Matrix Gla Protein gene from Xenopus laevis. Functional analysis of the promoter identifies a calcium sensitive region required for basal activity [16].

References