Browsing by Subject "Twisted Gastrulation"
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Item The Regulation And Function Of Bmps In Osteoclastogenesis(2019-06) Huntley, RaphaelBone morphogenetic proteins (BMPs) play a large role in the formation and maintenance of the skeleton, and, in recent years, have become a common clinical adjuvant. The regulatory processes tightly control BMP gradients, which can stimulate both osteoblasts to build bone, and osteoclasts to resorb bone. This thesis discusses data from multiple in-vitro and in-vivo BMP-related knockout models to elucidate the different function BMPs have on osteoclast differentiation and activity. We elucidate the mechanism by which BMP signaling is tightly controlled by Twisted Gastrulation, an extracellular BMP binding protein. Using an murine model we also show osteoclast derived BMP2 acts to regulate bone mineral density in-vivo, and can function to coordinate osteoblast matrix deposition.Item The regulation of osteoclastogenesis by bone morphogenetic proteins, twisted gastrulation, and histone deacetylases.(2012-08) Pham, Lan DangBone morphogenetic proteins (BMPs) are well-studied regulators of osteoblasts, and are used in a number of craniofacial and orthopedic procedures to promote localized bone formation. Studies of skeletal tissue has shed light on BMPʼs role as an inducer of chondrocytic and osteoblastic differentiation and function. BMPs have been used successfully in studies to: treat critical sized defects in both long and craniofacial bones; enhance fracture healing; treat nonunions and lumbar spinal fusion; and regenerate alveolar bone and portions of teeth such as dentin and pulp. However, it has been difficult to determine the optimal concentrations, appropriate temporal release, and regulation of BMPs, as both a deficiency and an excess of BMPs may lead to pathologic states. Furthermore, the cellular and molecular origin of this BMP-associated stimulation of bone resorption remains poorly understood. The data presented in this thesis will help us better understand the modulation of osteoclastogenesis and bone resorption by the regulatory proteins BMP-2, Twisted gastrulation, and Histone deacetylase 3 and 7. The knowledge gained by studying these regulators in osteoclasts should provide important new insight into the use of BMPs in bone generation procedures, its role in pathogenesis of bone resorptive disorders, and provide a conceptual framework for the development of successful therapies and bone regenerative strategies for diseases associated with increased bone loss and defective bone formation.Item Role of twisted gastrulation and matrix gamma-carboxyglutamic acid protein in bone homeostasis.(2012-05) Sotillo Rodriguez, Julio EliezerThe 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.