alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling.
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.
Szweras
Melanie
M
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Liu
Danmei
D
Partridge
Emily A
EA
Pawling
Judy
J
Sukhu
Balram
B
Clokie
Cameron
C
Jahnen-Dechent
Willi
W
Tenenbaum
Howard C
HC
Swallow
Carol J
CJ
Grynpas
Marc D
MD
Dennis
James W
JW
D017667:Adipocytes / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism; D002455:Cell Division; D019902:Chondrocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004838:Epiphyses / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010641:Phenotype; D013053:Spectrophotometry; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D060749:alpha-2-HS-Glycoprotein; D000509:alpha-Fetoproteins / Q000378:metabolism*
C556357:Ahsg protein, mouse; D001798:Blood Proteins; D016207:Cytokines; D016212:Transforming Growth Factor beta; D060749:alpha-2-HS-Glycoprotein; D000509:alpha-Fetoproteins