MOLECULAR MECHANISMS OF MATRIX GLA PROTEIN

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Calcification of vessels and cardiac valves causes a multitude of clinical problems including congestive heart failure, cardiomyopathy, angina, and complications during interventional and surgical procedures. Currently, there are no medical therapies able to prevent or reverse calcification. An understanding of the underlying mechanisms would identify new targets for developments of such therapies. Mice deficient in Matrix GLA Protein (MGP) develop extensive vascular calcification with replacement of the vascular wall by typical cartilage cells. This suggests that MGP plays a role in vascular cell differentiation. We hypothesize that the function of MGP is to act as an inhibitor of bone morphogenetic protein 2 (BMP-2), a potent inducer of calcified tissues. In absence of MGP, vascular cells may be induced by BMP-2, and differentiate into cartilage and bone cells instead of vascular smooth muscle cells. We hypothesize that this effect of MGP occurs early in vessel formation. The proposal has four aims. The first is to study the effect of increased levels of MGP on cell differentiation induced by BMP-2 in tissue culture, and then use this system to identify key sequences in MGP by altering the MGP protein. The second aim is to characterize the putative binding between MGP and BMP-2 by using cross-linking and binding studies. The third aim is to identify when in the development of MGP deficient mice, vascular cells lose their normal characteristics and differentiate into cartilage cells, using specific markers for smooth muscle and cartilage cells. Finally, we will generate transgenic mice deficient in normal MGP but expressing selected key sequences of MGP identified in previous aims to affect cell differentiation, and to study the effect of these sequences on in vascular calcification in vivo. Understanding the molecular mechanisms of MGP will provide information that is widely applicable to the development of vascular disease.