α2-HS Glycoprotein/Fetuin, a Transforming Growth Factor-β/Bone Morphogenetic Protein Antagonist, Regulates Postnatal Bone Growth and Remodeling*

Soluble transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP)-binding proteins are widely distributed in mammalian tissues and control cytokine access to membrane signaling receptors. The serum and bone-resident glycoprotein α2-HS-glycoprotein/fetuin (ASHG) binds to TGF-β/BMP cytokines and blocks TGF-β1 binding to cell surface receptors. Therefore, we examined bone growth and remodeling phenotypes in ASHG-deficient mice. The skeletal structure of Ahsg−/−mice appeared normal at birth, but abnormalities were observed in adult Ahsg−/−mice. Maturation of growth plate chondrocytes was impaired, and femurs lengthened more slowly between 3 and 18 months of age in Ahsg−/−mice. However, bone formation was increased in Ahsg−/−mice as indicated by greater cortical thickness, accelerated trabecular bone remodeling, and increased osteoblast numbers on bone surfaces. The normal age-related increase in cortical thickness and bone mineral density was accelerated in Ahsg−/−mice and was associated with increased energy required to fracture. Bone formation in response to implanted BMP cytokine extended further from the implant in Ahsg−/−compared with Ahsg+/+mice, confirming the interaction between ASHG and TGF-β/BMP cytokines in vivo. Our results demonstrate that ASHG blocks TGF-β-dependent signaling in osteoblastic cells, and mice lacking ASHG display growth plate defects, increased bone formation with age, and enhanced cytokine-dependent osteogenesis.