TRANSGENIC MODELS WITH SKELETAL REPAIR PHENOTYPES

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Formation of the proper tooth shape and cellular composition involves a highly ordered and regulated process. Regulation occurs within epithelial/mesenchymal interactions involving signaling proteins. Many of the proteins are growth factors which are involved in tooth development and play key roles in bone formation. One such growth factor important in teeth as well as bones, is transforming growth factor beta (TGF-beta). Transgenic animal models that contain a transgene driven by the osteocalcin promoter, which directs specific expression in odontoblasts, cementoblasts, and osteoblasts have been =created to study the effects of TGF-beta in bone. These mice models will be used to study the role of TGF-beta in dentin and cementum. The transgenes (and resultant mouse models) are as follows: 1) a dominant negative form of the type II TGF- beta in bone. These mice models will be used to study the role of TGF- beta in dentin and cementum. The transgenes(and resultant mouse models) are as follows: 1) a dominant negative form of the type II TGF-beta receptor (IIRDN mice), 2) a constitutively active TGF-beta2 ligand (TGF- beta2 mice), or 3) a cross dentin, cementum, and bone, suggests that phenotypic changes would occur in the teeth (as shown in bone) of these transgenic mice. Our preliminary studies have supported this hypothesis, and have shown that the dentin of the IIRDN mice is harder than dentin from the wild type mice. The specific aims of the proposal are as follows: (1) to determine the role of TGF-beta in the formation of mineralized tissues by studying the teeth of the IIRDN, TGF-beta2, and IIRDNxTGF-beta2 transgenic mouse models; (2) to elucidate the role of TGF-beta in repair of mineralized tissues by examining reparative dentin formation in IIRDN, TGF-beta2, and IIRDNxTGF-beta2 transgenic mouse models; (3) to develop a screening protocol for defects in mineralized tissues in other available transgenic mice models. Histomorphometry, microimaging, and hardness measurements will be utilized to understand the mechanism by which TGF- beta controls the formation of mineralizing tooth matrices. Further studies with the three types of mice as an approximately phenotypic series will allow us to better understand the role of TGF- beta and individual cell types in tooth structure and function in vivo. In addition, these studies will allow us to develop tools for screening teeth from other transgenic mice with bone repair defects available through the UCSF scientific community.