Neuropeptide Y (NPY) has been shown to play a critical role in the regulation of bone metabolism by signalling via Y1 and Y2 receptors. Centrally, hypothalamic Y2 but not Y1 receptors are important for the action of NPY on bone formation and osteoblast activity. This project investigates how the NPY system, in particular, the Y1 receptor, influences bone metabolism peripherally by examining a range of conditional and germline knockout mice using in vitro and in vivo techniques. Revealing the possibility of a direct role for the Y1 receptor on bone cells, we demonstrate the presence of Y1 but not Y2 receptor mRNA in osteoblasts by in situ hybridisation on femur sections and RT-PCR on bone marrow stromal cells (BMSCs). In addition, we show that NPY mRNA is also expressed by osteoblasts suggesting that locally produced NPY may directly influence bone cell activity. In order to investigate the role of osteoblastic Y1 receptors, mice with selective osteoblastic deletion of the Y1 receptor under control of the osteoblast-specific α1(I)-collagen promotor were generated. In male mice, osteoblast-specific Y1 receptor deletion resulted in a marked increase in femoral trabecular bone volume, trabecular number, cortical bone volume and cortical thickness due to elevated osteoblast activity as shown by increased mineral apposition rate and bone formation rate. Further in vitro investigations using cells isolated from germline and conditional knockout mice demonstrated that NPY inhibits the proliferation of BMSCs via the Y1 receptor and that mineralisation is enhanced in vitro in the absence of NPY or osteoblastic Y1 receptors. Moreover, this study reveals a critical role for the NPY system via Y1 receptors in the proliferation and differentiation of mesenchymal stem cells and osteoprogenitor cells. Together these data demonstrate a direct role for the NPY system via Y1 receptors on the proliferation and differentiation of osteoblastic progenitor cells as well as on regulating the activity of mature osteoblasts, thereby altering bone formation both in vitro and in vivo. Understanding the action of NPY on osteoblasts to regulate bone metabolism could have powerful therapeutic implications for stimulating bone accrual in diseases such as osteoporosis.

The success of orthopaedic implants fixed in the skeletal system using bone ingrowth into porous surfaces is critically dependent on the extent and quality of the initial bone ingrowth and the subsequent long-term maintenance of the bone within the porous structure. Biologically-significant elements (Ca, Mg, Mn) were incorporated at concentrations up to 5 mol% in solid solution in yttia-stabilised tetragonal zirconia polycrystal (3YTZP), whilst controlling microstructure and phase composition, to investigate the effect of ceramic chemistry on cellular behaviour in vitro and bone ingrowth into porous structures in vivo. Cellular attachment, proliferation, and migration on the ceramics were investigated using in vitro assays using fibroblasts. Cells were able to adhere strongly and proliferate on all ceramic surfaces, exhibiting maximal proliferation and minimal migration on 3YTZP but significantly faster migration on doped-3YTZP. The TZP ceramics were therefore considered to support normal cellular processes and thus were suitable for further study in vivo. A technique based on pressure casting ceramic slurry into a polymer preform of the desire pore structure, followed by polymer burnout and then sintering, was developed for fabricating porous bioceramics containing highly-controlled three-dimensional pore geometries. The ability of a selected pore structure to support bone ingrowth was tested using hydroxyapatite by implanting samples into femoral cortical bone of adult sheep for 4 and 12 weeks. Bone was able to rapidly colonise the porous structure and remodel such that, by 12 weeks implantation time, the majority of the porosity was filled with mature lamellar bone. Porous scaffolds of pure 3YTZP and 3YTZP doped with 1 mol% Mg, 1 mol% Mn, 1 mol% Ca, or 5 mol% Ca were fabricated and tested in the sheep model. Bone ingrowth into the doped compositions was significantly greater than that into pure 3YTZP, and was similar to that into the porous hydroxyapatite, indicating that the dopants significantly promoted osteogenesis within the bioinert scaffolds. This finding has application in clinical applications in that the initial bone ingrowth and, potentially, the long-term maintenance of bone within the porous structure may be improved by the incorporation of small amounts of biologically significant elements.

Thesis (Ph. D.)--University of Adelaide, 1987. / Includes bibliographical references (leaves 196-251).

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 163-184) Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 113-131) Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 109-154) Also available in print.

Thesis (M.S.)--Central Connecticut State University, 1999. / Thesis advisor: Kathy Martin-Troy. " ... in partial fulfillment of the requirements for the degree of Master of Science in Biology." Includes bibliographical references (leaves 56-62).