The role of Fetuin-A in ectopic calcification and lipid metabolism

Fetuin-A is a hepatic serum protein playing a major role in mineralized matrix metabolism. It acts as a mineral chaperone mediating the stabilization of protein- mineral complexes and their clearance from circulation. Fetuin-A deficient mice on the genetic background DBA/2 develop severe soft tissue calcification particularly in highly capillarized and metabolically active tissues. Additional deletion of fetuin-A in a mouse model of atherosclerosis, the Apoe-/- C57BL/6 mouse, results in a model organism for calcifying atherosclerosis.Different therapeutic strategies were tested regarding their ability to inhibit development of calcified lesions in DBA/2,Ahsg-/- mice. These strategies included sodium thiosulfate as a potential therapeutic agent in the treatment of calciphylaxis, fetuin-A as a systemic inhibitor of calcification, and magnesium as an inhibitor of calcification in vascular smooth muscle cells. Furthermore, the influence of phosphate was analyzed. Rivaroxaban®, an anticoagulant inhibiting blood clotting factor Xa, was used to test the involvement of blood coagulation in calcification. This was studied, because calcified lesions first develop in the lumen of microvessels, and lesions contain blood coagulation factors. Soft tissue calcification was scored in vivo by CT and fluorescence molecular tomography (FMT) employing labeled fetuin-A as a molecular probe for calcified matrix. Post mortem analysis included chemical calcium quantification and histochemistry of tissue sections. While sodium thiosulfate and Rivaroxaban® treatment did not affect calcification, magnesium, low phosphate diet and fetuin-A reduced the calcification burden significantly. C57BL/6,Apoe-/-/Ahsg-/- mice were used to investigate the influence of anticoagulants and fetuin-A in atherosclerosis. Previous publications reported that high serum fetuin-A levels are associated with insulin resistance and metabolic syndrome. A recent study comparing Apoe-/- and Apoe-/-/Ahsg-/- mice showed that fetuin-A is involved in lipid metabolism in that Apoe-/-/Ahsg-/- mice had increased serum cholesterol levels suggesting impaired reverse cholesterol transport. In this current study Apoe-/-/Ahsg-/- mice had serum cholesterol levels similar to those of single knockout mice. Instead, the presence of fetuin-A seemed to exacerbate atherosclerosis. I hypothesize that fetuin-A by exerting its role as a lipidic mineral debris carrier may inadvertently enhance lipidic mineral debris uptake into plaque macrophages leading to increased plaque size and increased calcification