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      Regulatory inhibition of biological tissue mineralization by calcium phosphate through post-nucleation shielding by Fetuin-A

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          Abstract

          In vertebrates, insufficient availability of calcium and phosphate ions in extracellular fluids leads to loss of bone density and neuronal hyper-excitability. To counteract this problem, calcium ions are present at high concentrations throughout body fluids -- at concentrations exceeding the saturation point. This condition leads to the opposite situation where unwanted mineral sedimentation may occur. Remarkably, ectopic or out-of-place sedimentation into soft tissues is rare, in spite of the thermodynamic driving factors. This fortunate fact is due to the presence of auto-regulatory proteins that are found in abundance in bodily fluids. Yet, many important inflammatory disorders such as atherosclerosis and osteoarthritis are associated with this undesired calcification. Hence, it is important to gain an understanding of the regulatory process and the conditions under which it can go awry. In this manuscript, we adapt mean-field classical nucleation theory to the case of surface-shielding in order to study the regulation of sedimentation of calcium phosphate salts in biological tissues through the mechanism of post-nuclear shielding of nascent mineral particles by binding proteins. We develop a mathematical description of this phenomenon using a countable system of hyperbolic partial differential equations. A critical concentration of regulatory protein is identified as a function of the physical parameters that describe the system.

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          The kinetics of precipitation from supersaturated solid solutions

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            Ion-association complexes unite classical and non-classical theories for the biomimetic nucleation of calcium phosphate.

            Despite its importance in many industrial, geological and biological processes, the mechanism of crystallization from supersaturated solutions remains a matter of debate. Recent discoveries show that in many solution systems nanometre-sized structural units are already present before nucleation. Still little is known about the structure and role of these so-called pre-nucleation clusters. Here we present a combination of in situ investigations, which show that for the crystallization of calcium phosphate these nanometre-sized units are in fact calcium triphosphate complexes. Under conditions in which apatite forms from an amorphous calcium phosphate precursor, these complexes aggregate and take up an extra calcium ion to form amorphous calcium phosphate, which is a fractal of Ca(2)(HPO(4))(3)(2-) clusters. The calcium triphosphate complex also forms the basis of the crystal structure of octacalcium phosphate and apatite. Finally, we demonstrate how the existence of these complexes lowers the energy barrier to nucleation and unites classical and non-classical nucleation theories.
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              The role of prenucleation clusters in surface-induced calcium phosphate crystallization.

              Unravelling the processes of calcium phosphate formation is important in our understanding of both bone and tooth formation, and also of pathological mineralization, for example in cardiovascular disease. Serum is a metastable solution from which calcium phosphate precipitates in the presence of calcifiable templates such as collagen, elastin and cell debris. A pathological deficiency of inhibitors leads to the uncontrolled deposition of calcium phosphate. In bone and teeth the formation of apatite crystals is preceded by an amorphous calcium phosphate (ACP) precursor phase. ACP formation is thought to proceed through prenucleation clusters--stable clusters that are present in solution already before nucleation--as was recently demonstrated for CaCO(3) (refs 15,16). However, the role of such nanometre-sized clusters as building blocks for ACP has been debated for many years. Here we demonstrate that the surface-induced formation of apatite from simulated body fluid starts with the aggregation of prenucleation clusters leading to the nucleation of ACP before the development of oriented apatite crystals.
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                Author and article information

                Journal
                2015-01-11
                2016-03-13
                Article
                1501.02526
                efd34703-75ea-40ab-a0a0-ed4661f0902b

                http://arxiv.org/licenses/nonexclusive-distrib/1.0/

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                Custom metadata
                This paper has been withdrawn due to errors in determining parameters from the literature
                cond-mat.soft math.AP physics.bio-ph physics.chem-ph q-bio.TO

                Analysis,Condensed matter,Physical chemistry,Biophysics,Life sciences
                Analysis, Condensed matter, Physical chemistry, Biophysics, Life sciences

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