Abstract
The serum protein fetuin-A is a potent systemic inhibitor of soft tissue calcification. Fetuin-A is highly effective in the formation and stabilization of protein-mineral colloids, referred to as calciprotein particles (CPPs). These particles ripen in vitro in a two-step process, indicated by a morphological conversion from spheres to larger prolate ellipsoids. Using a combined light scattering and electron microscopic imaging approach we determined that the second-stage particles resulted from a highly anisotropic outgrowth of the first-stage particles. Electron microscopy of ascites fluid from a patient with calcifying peritonitis revealed particles reminiscent of secondary CPPs. Thus, CPPs form in the body and undergo the two-step ripening at least in pathological conditions. Unlike in vitro generated CPPs, ascites-derived CPPs contained little fetuin-A but large amounts of albumin. This prompted us to study the role of fetuin-A combined with other serum proteins in CPP formation. Fetuin-A was indispensable for primary CPP formation. Albumin and acidic proteins in general greatly enhanced the fetuin-A triggered formation of secondary CPPs and, thus, substituted substantial amounts of fetuin-A without loss of inhibition of calcium phosphate precipitation. Thus, direct mineral deposition from solute in the body is unlikely even at low fetuin-A serum levels as long as sufficient bulk acidic protein is available. Collectively fetuin-A and other acidic bulk plasma proteins may be considered as mineral chaperones mediating the stabilization, safe transport, and clearance in the body of calcium and phosphate as colloidal complexes, thus, preventing ectopic calcification.
Highlights
Trolled mineral deposition in the blood or in the soft tissue would inevitably occur causing ectopic calcification
Its high affinity for bone mineral (9) and the ability to prevent the precipitation of basic calcium phosphates from supersaturated solutions suggested that fetuin-A was a potent systemic inhibitor of soft tissue calcification (5, 10 –12)
We found that the size of the shorter semi-axis b of the secondary calciprotein particles (CPPs) was very close to the radius of the primary CPPs, suggesting that the secondary CPPs were formed by anisotropic growth of the primary particles, probably induced by crystallization
Summary
Trolled mineral deposition in the blood or in the soft tissue would inevitably occur causing ectopic calcification. Its high affinity for bone mineral (9) and the ability to prevent the precipitation of basic calcium phosphates from supersaturated solutions suggested that fetuin-A was a potent systemic inhibitor of soft tissue calcification (5, 10 –12). Fetuin-A has an exceptionally high affinity for basic calcium phosphate mineral surfaces irrespective of the exact composition and texture, e.g. synthetic apatite, bone mineral, or calciprotein-like particles (4, 17, 18, 20, 21). These studies suggested that the fetuin-A and albumin co-localized with mineral at ratios varying over a wide range. Based on the results of these studies, we propose a refined model of systemic calcification inhibition implying cooperative effects of acidic serum proteins and fetuin-A as a key player
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