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Originally published In Press as doi:10.1074/jbc.M112234200 on March 18, 2002

J. Biol. Chem., Vol. 277, Issue 22, 19991-19997, May 31, 2002
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alpha 2-HS Glycoprotein/Fetuin, a Transforming Growth Factor-beta /Bone Morphogenetic Protein Antagonist, Regulates Postnatal Bone Growth and Remodeling*

Melanie SzwerasDagger §, Danmei LiuDagger , Emily A. PartridgeDagger , Judy PawlingDagger , Balram SukhuDagger , Cameron Clokie||, Willi Jahnen-Dechent**, Howard C. TenenbaumDagger ||, Carol J. SwallowDagger , Marc D. GrynpasDagger Dagger Dagger , and James W. DennisDagger §§§

From the Dagger  Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, the § Department of Molecular and Medical Genetics, the || Department of Dentistry, and the Dagger Dagger  Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and ** IZKF BIOMAT, Klinikum der RWTH Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany

Soluble transforming growth factor-beta (TGF-beta )/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 alpha 2-HS-glycoprotein/fetuin (ASHG) binds to TGF-beta /BMP cytokines and blocks TGF-beta 1 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-beta /BMP cytokines in vivo. Our results demonstrate that ASHG blocks TGF-beta -dependent signaling in osteoblastic cells, and mice lacking ASHG display growth plate defects, increased bone formation with age, and enhanced cytokine-dependent osteogenesis.

* This work was supported in part by grants from Canadian Institutes for Health Research (to J. W. D. and M. G.) and the Physicians Services Inc. (to C. J. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Canadian Institutes for Health Research studentship.

§§ To whom correspondence should be addressed. Tel.: 416-586-8233, Fax: 416-586-8588; E-mail: Dennis@mshri.on.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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