Role of twisted gastrulation and matrix gamma-carboxyglutamic acid protein in bone homeostasis.

Abstract

The regulation signaling activity of osteoblasts and osteoclasts has been linked to extracellular proteins, including twisted gastrulation (TWSG1) and matrix gamma-carboxyglutamic acid protein (MGP). TWSG1 is a regulator of bone morphogenetic proteins (BMPs) signaling activity. Previous studies have shown that TWSG1 is an essential modulator of not only skeletal development but also soft tissue development (i.e. salivary gland). MGP is a vitamin K-dependent protein previously characterized as a potent inhibitor of biomineralization. Numerous cells types produce MGP, including osteoblasts, chondrocytes, vascular smooth muscle cells and endothelial cells. Despite current research, little is known about the effects of TWSG1 and MGP on the regulation of osteoblasts and osteoclasts. Both of which are cells that maintain bone remodeling. In this dissertation, we assessed the role of both TWSG1 and MGP in postnatal bone homeostasis as well as in vitro functional analysis of TWSG1 and MGP on osteoblasts and osteoclasts. We were able to determine that the C57BL/6 MGP deficient mice and 129Sv/Ev TWSG1 deficient mice exhibited an osteopenic skeletal phenotype. This phenotype was explained by an imbalance in the cellular regulatory patterns associated with the regulation of homeostatic bone remodeling. Further, we characterized cellular pathways which explained how, in both TWSG1 and MGP deficient mice, excessive osteoclastic activity was the name culprit in the osteopenic phenotypes. Taken together, our results highlight the importance in the modulation of osteoblastic and osteoclastic activity by TWSG1 and MGP.