Biological implications of fetuin for bone remodeling system and possible evidence for its use in heterotopic ossification

Fetuin is an α2-Heremans–Schmid glycoprotein (α2-HS), a non-collagenous serum protein in human blood and calcified tissue. Fetuins form highly specific complexes, and fetuin matrix γ-glutamic acid (Gla) protein complex prevents the growth, aggregation and precipitation of calcified components. Fetuin binds to TGF-β/BMP, and the binding order is BMP-2 > BMP-4 > BMP-6 > FGF-β1 > TGF-β2. The biphasic osteogenic response to TGF-β1 suggests overlapping gradients of TGF-β1/BMP. Elevated serum fetuin levels are correlated with common features of osteogenesis imperfecta and patients with Albright osteodystrophy may use fetuin to prevent osteoblastic differentiation. Patients with Paget's disease, involving increased bone turnover, show depressed fetuin levels. Fetuin A is an important circulating inhibitor of calcification in vivo, and is down-regulated during the acute-phase response. There is a hypothesis that fetuin deficiency is directly related to uremic vascular calcification. At present, in cases of bone disorders (heterotopic ossification) for which there is no recommended surgery, such as Albright syndrome and vascular ossification, clinical use of fetuin might reduce the risk of extensive heterotopic ossification.