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

Melanie Szweras,Danmei Liu,Emily A Partridge,Judy Pawling,Balram Sukhu,Cameron Clokie,Willi Jahnen-Dechent,Howard C Tenenbaum,Carol J Swallow,Marc D Grynpas,James W Dennis

doi:10.1074/jbc.m112234200

Abstract

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 alpha2-HS-glycoprotein/fetuin (ASHG) binds to TGF-beta/BMP cytokines and blocks TGF-beta1 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.

Highlights

Soluble transforming growth factor-␤ (TGF-␤)/bone morphogenetic protein (BMP)-binding proteins are widely distributed in mammalian tissues and control cytokine access to membrane signaling receptors
Our results demonstrate that ASHG blocks TGF-␤-dependent signaling in osteoblastic cells, and mice lacking ASHG display growth plate defects, increased bone formation with age, and enhanced cytokine-dependent osteogenesis
Because polymorphic differences in the coding region of human AHSG correlate with differences in stature, we examined femur growth plate histology and dimensions in the mice

Summary

Introduction

Soluble transforming growth factor-␤ (TGF-␤)/bone morphogenetic protein (BMP)-binding proteins are widely distributed in mammalian tissues and control cytokine access to membrane signaling receptors. Our results demonstrate that ASHG blocks TGF-␤-dependent signaling in osteoblastic cells, and mice lacking ASHG display growth plate defects, increased bone formation with age, and enhanced cytokine-dependent osteogenesis. Ectopic bone formation in response to intramuscular BMP cytokine implants was enhanced in ASHG-deficient mice, consistent with loss of a negative regulator of osteogenesis.

Results

Conclusion