Formation of Calcium Phosphate Minerals in the Presence of Fetuin-A

Abstract

Mineral formation is regulated by molecular based promoters or inhibitors in biological systems. Among serum proteins, fetuin-A can effectively inhibit unwanted calcification in vivo via forming fetuin-mineral complexes called calciprotein particles (CPPs). Here, the formation and phase transformation mechanisms of CPPs are investigated in detail by combining in situ potentiometric measurements and solid phase characterization. It is found that fetuin-A inhibits mineral formation via affecting both thermodynamic and kinetic factors of precipitation. A better understanding of the reaction pathway as well as the interactions between the mineral and protein counterparts can potentially inform the development of in vitro model systems of biomineralization and pave the way for the development of new therapies to treat ectopic calcification.

Keywords

• biomineralization
• calcium phosphate
• fetuin-A
• mineral formation

Supporting Institution

The Research Council of Norway

Project Number

295864

References

1. 1. Mann, S., 1988, Molecular recognition in biomineralization. Nature, 332(6160): p. 119-124.
2. 2. Vasquez, E.S., et al., 2015, Fetuin-A adsorption and stabilization of calcium carbonate nanoparticles in a simulated body fluid. Journal of Materials Chemistry B, 3(31): p. 6411-6419.
3. 3. Eidelman, N., L.C. Chow, and W.E. Brown, 1987, Calcium phosphate saturation levels in ultrafiltered serum. Calcified Tissue International, 40(2): p. 71-78.
4. 4. Cai, M.M., E.R. Smith, and S.G. Holt, 2015, The role of fetuin-A in mineral trafficking and deposition. Bonekey Rep, 4: p. 672.
5. 5. Xu, A.-W., Y. Ma, and H. Cölfen, 2007, Biomimetic mineralization. Journal of Materials Chemistry, 17(5): p. 415-449.
6. 6. Gelli, R., F. Ridi, and P. Baglioni, 2019, The importance of being amorphous: calcium and magnesium phosphates in the human body. Advances in Colloid and Interface Science, 269: p. 219-235.
7. 7. Trepanowski, J.F., J. Mey, and K.A. Varady, 2015, Fetuin-A: a novel link between obesity and related complications. International Journal of Obesity, 39(5): p. 734-741.
8. 8. Heiss, A., et al., 2003, Structural basis of calcification inhibition by α2-HS glycoprotein/fetuin-A: Formation of colloidal calciprotein particles. Journal of Biological Chemistry, 278(15): p. 13333-13341. 9. Brylka, L. and W. Jahnen-Dechent, 2013, The Role of Fetuin-A in Physiological and Pathological Mineralization. Calcified Tissue International, 93(4): p. 355-364.

9. 10. Schinke, T., et al., 1996, The serum protein α2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. Journal of Biological Chemistry, 271(34): p. 20789-20796.
10. 11. Seto, J., et al., 2012, Accelerated Growth Plate Mineralization and Foreshortened Proximal Limb Bones in Fetuin-A Knockout Mice. PLoS ONE, 7(10).
11. 12. Price, P.A. and J.E. Lim, 2003, The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex. Journal of Biological Chemistry, 278(24): p. 22144-22152.
12. 13. Rochette, C.N., et al., 2009, A shielding topology stabilizes the early stage protein-mineral complexes of fetuin-A and calcium phosphate: A time-resolved small-angle x-ray study. ChemBioChem, 10(4): p. 735-740.
13. 14. Pasch, A., et al., 2012, Nanoparticle-Based Test Measures Overall Propensity for Calcification in Serum. Journal of the American Society of Nephrology, 23(10): p. 1744-1752.
14. 15. Heiss, A., et al., 2007, Structural dynamics of a colloidal protein-mineral complex bestowing on calcium phosphate a high solubility in biological fluids. Biointerphases, 2(1): p. 16-20.
15. 16. Ucar, S., et al., 2019, Formation of Hydroxyapatite via Transformation of Amorphous Calcium Phosphate in the Presence of Alginate Additives. Crystal Growth and Design, 19(12): p. 7077-7087.
16. 17. Chen, Y., et al., 2014, Stabilizing amorphous calcium phosphate phase by citrate adsorption. CrystEngComm, 16(10): p. 1864-1867.
17. 18. Fang, W., et al., 2016, Hydroxyapatite Crystal Formation in the Presence of Polysaccharide. Crystal Growth & Design, 16(3): p. 1247-1255.
18. 19. Hu, Q., et al., 2012, The thermodynamics of calcite nucleation at organic interfaces: Classical vs. non-classical pathways. Faraday Discussions, 159: p. 509-523.
19. 20. Zou, Z., et al., 2018, Additives influence the phase behavior of calcium carbonate solution by a cooperative ion-association process. Journal of Materials Chemistry B, 6(3): p. 449-457.
20. 21. Ibsen, C.J.S., D. Gebauer, and H. Birkedal, 2016, Osteopontin Stabilizes Metastable States Prior to Nucleation during Apatite Formation. Chemistry of Materials, 28(23): p. 8550-8555.
21. 22. Ding, H., et al., 2014, Toward a Detailed Understanding of Magnesium Ions on Hydroxyapatite Crystallization Inhibition. Crystal Growth & Design, 14(2): p. 763-769.