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This dissertation, Molecular Basis for the Increased Osteoblast Activity in a Mouse Model With Hyperostosis by Yin-wo, Cheng, 鄭燕和, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled MOLECULAR BASIS FOR INCREASED OSTEOBLAST ACTIVITY IN A MOUSE MODEL WITH HYPEROSTOSIS Submitted by CHENG YIN WO for the degree of Master of Philosophy at The University of Hong Kong in August 2005 Transgenic mice (13del-tg), expressing a Col10a1-13del transgene with a p.T619fsX672 mutation in type X collagen, exhibit postnatal generalized progressive hyperostosis. The transgene is expressed in hypertrophic chondrocytes as expected. However, it is also expressed ectopically in osteocytes that may be associated with hyperostosis, with activation of osteoblast activity. Histological analyses showed active lateral bone growth associated with an increase in numbers of pre-osteoblasts and osteoblasts at sites of bone formation. Moreover, cortical bones contained many newly formed osteocytes and osteoids, indicating a more active bone remodeling process in 13del-tg mice than wild-type. Analyses of specific markers showed alterations in the TGF-β and BMP signaling pathways that may promote the recruitment of osteoblast precursor cells to sites of bone synthesis such as in the periosteum and the lacunae; with the activation of Runx2, a key transcription factor controlling osteoblast differentiation and synthesis of extracellular matrix (ECM) components of bone. There is an increased proliferation of osteogenic cells associated with an elevated expression of the ECM components such as type I collagen, osteopontin and osteocalcin in the periosteum and in the lacunae of 13del-tg femurs. Given that TGF-β signaling is upstream of Runx2, we hypothesize that the expression of the transgene in osteocytes, by a mechanism yet to be identified, activates TGF-β signaling, thus initiating the cascade of events culminating in hyperostosis. To demonstrate the expression of the transgene in osteocytes is directly associated OSB with hyperostosis, twelve transgenic mice (13del ) expressing the Col10a1-13del transgene specifically in osteoblasts, under regulation by an osteocalcin promotor, were created. However, due to time limitation, the expression and phenotype characterization of these mice have not been assessed, but the information will provide important insights to the molecular basis for the generalized hyperostosis in 13del-tg mice, with the potential for discovering novel drugs or drug targets in the treatment of disorders where bone mass is affected. DOI: 10.5353/th_b3461298 Subjects: Bone cells - Molecular aspectsExostosis - Molecular aspectsTransgenic mice - Molecular aspects

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