Fetuin-A Regulation of Calcified Matrix Metabolism

Abstract

The final step of biomineralization is a chemical precipitation reaction that occurs spontaneously in supersaturated or metastable salt solutions. Genetic programs direct precursor cells into a mineralization-competent state in physiological bone formation (osteogenesis) and in pathological mineralization (ectopic mineralization or calcification). Therefore, all tissues not meant to mineralize must be actively protected against chance precipitation of mineral. Fetuin-A is a liver-derived blood protein that acts as a potent inhibitor of ectopic mineralization. Monomeric fetuin-A protein binds small clusters of calcium and phosphate. This interaction results in the formation of prenucleation cluster-laden fetuin-A monomers, calciprotein monomers, and considerably larger aggregates of protein and mineral calciprotein particles. Both monomeric and aggregate forms of fetuin-A mineral accrue acidic plasma protein including albumin, thus stabilizing supersaturated and metastable mineral ion solutions as colloids. Hence, fetuin-A is a mineral carrier protein and a systemic inhibitor of pathological mineralization complementing local inhibitors that act in a cell-restricted or tissue-restricted fashion. Fetuin-A deficiency is associated with soft tissue calcification in mice and humans.

Serum Calcification Propensity Is a Strong and Independent Determinant of Cardiac and All-Cause Mortality in Kidney Transplant Recipients

“…negative acute-phase reactant (36). The levels of CPPs are related to inflammation (22,37), and secondary CPPs induce an inflammatory response when exposed to macrophages in vitro (38).…”

The multiple effects of amino acids on the early stages of calcium carbonate crystallization

“…The composition of the biomineralization-related proteins are completely varied across species, however, many are found to have common characteristics such as highly glycosylated, acidic [15] and anionic functional groups [16][17][18]. The exact roles of these macromolecules are still unknown while what is known, is that this fraction is necessary for normal mineralized tissue growth and development, as well as its materials properties [19][20][21][22]. There are no consistent compositions or structural homologs found amongst these organic fractions, except that they do have regions which are highly repetitive and have characteristics of "intrinsically disordered protein" (IDP) domains, domains implicated in either mineral binding or the assembly process [23][24][25].…”

A materials science vision of extracellular matrix mineralization

“…A single molecule of fetuin A can sequester up to 90-120 calcium atoms and 54-72 phosphate ions 24 . Fetuin A with calcium and phosphate ions forms colloidal complexes (calciprotein particles) about 30-150 nm in size 25 . Fetuin A has a strong affinity for bone tissue and comprises up to 25% of the noncollagenous proteins of bone 25 .…”

“…The pro-mineralization agents include ubiquitous calcium and phosphate ions, and a collagen-and elastin-rich tissue framework. These are opposed by anti-mineralization factors, both systemic (PPi and fetuin A) 25 and local (MGP) 35 . Local nucleators of mineralization, such as thrombi, cell debris, matrix vesicles and activated platelets may favour calcium phosphate mineral nucleation upon local trauma or necrosis 78 .…”

“…The thickness of all three layers does not normally exceed 1 mm in humans; the leaflets are avascular and receive the nutrients by diffusion from the nearby passing blood. 25 . In cardiovascular tissues, mineralization is further prevented by the resident cells, vascular smooth muscle cells which secrete local inhibitors such as matrix Gla protein 35 .…”