Matrix gla protein

Matrix Gla protein (MGP) is a vitamin K-dependent protein that is synthesized in bone and many other mesenchymal cells and is also highly expressed in vascular smooth muscle cells (VSMCs) and chondrocytes. Numerous studies have confirmed that MGP acts as a calcification inhibitor, although the mechanism of action is not yet fully understood (Bjørklund G et al. 2020). MGP occurs in four forms, i.e. fully carboxylated (cMGP), undercarboxylated, i.e. weakly carboxylated (ucMGP), phosphorylated (pMGP) and non-phosphorylated (desphospho, dpMGP).

The modulation of tissue calcification by MGP may be regulated in several ways, including direct inhibition of calcium phosphate precipitation, formation of matrix vesicles (MVs), formation of apoptotic bodies (ABs) and transdifferentiation of VSMCs. The specific effect of MGP is not yet clear, but could be related to the functional inhibition of BMP-2 and BMP-4 by blocking the deposition of calcium crystals. In contrast to the coagulation factors, which are carboxylated in the liver, MGP and Gas-6 are carboxylated in the vascular system itself. This peripheral carboxylation process differs from hepatic carboxylation, but both are inhibited by the administration of warfarin. Warfarin prevents the activation of MGP and Gas-6 and leads to vascular calcification in animals. The relationship between warfarin and vascular calcification in humans has not yet been fully clarified (Danziger J 2008).

ELISA methods are currently available to detect the different types of MGP. The expression of the MGP gene can be regulated by different mechanisms that have the potential to become genomic biomarkers for predicting the progression of vascular calcification (VC). VC is a recognized risk factor for cardiovascular disease and is particularly common in patients with chronic kidney disease (CKD).

The ucMGP measured in plasma correlates directly with the availability of vitamin K. The uncarboxylated matrix Gla protein serves as a sensitive risk marker for cardiovascular diseases by allowing conclusions to be drawn about the physiological condition of the vessels. It acts as an important diagnostic predictor of adverse cardiovascular outcomes and mortality. The determination of the dp-ucMGP level is particularly recommended for older people who are prone to arteriosclerosis or patients with chronic kidney disease, diabetes mellitus or under treatment with warfarin or antibiotics in order to be able to assess the risk of vascular complications (Danziger J 2008).

Vitamin K-dependent proteins (VKDPs) must be carboxylated to become biologically active. Although coagulation factors are the best known VKDPs, there are many others with important physiological functions. Matrix Gla protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs. Both serve to protect the vascular system;

1. Bjørklund G et al. (2020) The Role of Matrix Gla Protein (MGP) in Vascular Calcification. Curr Med Chem 27:1647-1660.
2. Borrás T et al. (2015) A Novel Mgp-Cre Knock-In Mouse Reveals an Anticalcification/Antistiffness Candidate Gene in the Trabecular Meshwork and Peripapillary Scleral Region. Invest Ophthalmol Vis Sci 56: 2203-2214.
3. Danziger J (2008) Vitamin K-dependent proteins, warfarin, and vascular calcification. Clin J Am Soc Nephrol 3:1504-1510.
4. Luo G et al. (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nat 386: 78-81.
5. Schurgers LJ et al. (2007) Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 5:2503-11