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The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles CPP βrapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization calcification.
Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood.
Genome-wide expression analysis of calcified lesions and surrounding not calcified tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis.
Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.
