The Serum Protein α2-HS Glycoprotein/Fetuin Inhibits Apatite Formation in Vitro and in Mineralizing Calvaria Cells

Abstract

We present data suggesting a function of ␣ 2 -HS glycoproteins/fetuins in serum and in mineralization, namely interference with calcium salt precipitation. Fetuins occur in high serum concentration during fetal life. They accumulate in bones and teeth as a major fraction of noncollagenous bone proteins. The expression pattern in fetal mice confirms that fetuin is predominantly made in the liver and is accumulated in the mineralized matrix of bones. We arrived at a hypothesis on the molecular basis of fetuin function in bones using primary rat calvaria osteoblast cultures and salt precipitation assays. Our results indicate that fetuins inhibit apatite formation both in cell culture and in the test tube. This inhibitory effect is mediated by acidic amino acids clustering in cystatin-like domain D1. Fetuins account for roughly half of the capacity of serum to inhibit salt precipitation. We propose that fetuins inhibit phase separation in serum and modulate apatite formation during mineralization.

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

“…It is a general opinion, ensued from old findings [28,31] and confirmed by relatively recent studies [32,33], that fetuin-A is synthesized in the liver and is incorporated, via the bloodstream, into the bone matrix during the mineralization process, as a result of its high affinity for hydroxyapatite [2,12,34,35]. In the present study, most osteoblasts were immunostained for fetuin-A in all types of renal osteodystrophy, as well as in normal bone.…”

Fetuin-B, a second member of the fetuin family in mammals

“…Consistent with the importance of fetuins in development, AHSG is involved in osteogenesis and bone resorption [11,12]. These functions have been ascribed to the capacities of AHSG to control calcium-salt precipitation in blood [13] and to accumulate in bone matrix [14] as well as to counteract a transforming growth factor-β activity required for bone mineralization [12,15]. AHSG modulates some insulin-driven and kinase-mediated signal-transduction pathways, possibly in a tissue-specific fashion [16].…”

Mineralization of Decalcified Bone Occurs Under Cell Culture Conditions and Requires Bovine Serum But Not Cells

“…We speculate that the failure of some type I collagen structures to mineralize in vivo is due to the presence of powerful inhibitors of mineralization. Previous studies have shown that serum itself contains high levels of one potent inhibitor of hydroxyapatite formation, fetuin (a2-HS-glycoprotein) [28][29][30], and that the calcification of cartilage in vivo is normally prevented by the calcification inhibitory activity of the vitamin K-dependent matrix Gla protein [31,32]. It seems likely that type I collagen matrices that do not ordinarily calcify, such as tendon, contain other potent inhibitors of mineralization in vivo.…”