AHSG/Fetuin Regulates Ssteogenesis and Inflammation

grantor: University of TorontoAHSG/fetuin is a serum glycoprotein, which accumulates in mineralized bone and has been described as a reverse acute phase reactant. AHSG binds to TGF-ß/BMP cytokines 'in vitro', and suppresses TGF-ß-induced osteogenesis in bone marrow cell cultures. However, AHSG-deficient mice were recently reported to be anatomically normal at birth. In this study, I examined the effects of AHSG-deficiency on bone growth and homeostasis, as well as on the response to inflammatory agents, two compartments where TGF-ß/BMP cytokines are known to be active. AHSG-/- mice displayed abnormal chondrocyte organization in femoral growth plates and had shorter bones due to reduced bone growth in young mice. Furthermore, AHSG-deficient mice displayed increased bone remodeling and adipogenesis in the bone marrow. Three-point bending tests indicated that the material properties of AHSG -/- bones declined more rapidly with age compared to AHSG +/+ resulting in weaker bones. Histomorphometry of femoral bone sections revealed increased bone formation rates and osteoblasts/surface in AHSG -/- mice at 3 months of age, while formation rates were significantly less in AHSG+/- mice relative to AHSG +/+ mice. A model is proposed to accommodate this unusual gene dosage effect of AHSG, where an AHSG concentration gradient in the marrow regulates the availability of TGF-ß/BMP cytokines, and thereby the recruitment of osteoprogenitor cells during the bone remodeling process.Ph.D