Systemic inhibition of spontaneous calcification by the serum protein α₂-HS glycoprotein/fetuin

Summary

The extracellular fluid is a metastable system with regard to calcium and phosphate ions. Active inhibitors of calcification must be present in serum to prevent the spontaneous formation of Ca²⁺• P_i solid phases which could otherwise precipitate to cause renal calcinosis and block small blood vessels. α₂-HS glycoproteins/fetuins, AHSGs, are ideal candidates for this function. AHSGs are ubiquitous and highly abundant in serum; they bind calcium and efficiently prevent de novo formation of apatitic mineral. Normocalcemic AHSG-deficient mice develop sporadic perivascular calcification. Hypercalcemia induced by dietary means or by hormone treatment results in lethal calcinosis in Ahsg^−/− mice. A mineral binding structure is proposed for domain D1 of AHSG suggesting that the proposed EF-hand motif for calcium binding does not exist in AHSG. Unlike serum albumin, AHSG does hot preferentially bind ionic Ca²⁺, but rather in the form of apatitic microcrystals.