Development of new debris mediated human osteolysis model to investigate the potential therapeutic role of matrix metalloproteinase inhibitors in aseptic loosening

Developing medical treatment for aseptic loosening will not only require a better understanding of the biological process of aseptic loosening but also the development of an effective laboratory model to test the potential of these drugs. An optimal model should allow rapid multiple testing, be cost effective and simple. This thesis concentrates on the development of a new in vitro particle induced osteolysis model and the testing of potential pharmacological agents such as doxycycline and statins against this process.;The objectives of this study were to: 1. Investigate the ability of human interface membrane cells taken from aseptically loosened hip joints to resorb bone using an established radiolabelled murine calvaria model. 2. Investigate whether N-Telopeptides (NTx) can be used as an osteolysis marker instead of radioactive calcium for the investigation of aseptic loosening. 3. Develop a laboratory model of aseptic loosening using powdered human bone and NTx as an osteolysis marker. 4. Investigate the ability of doxycycline to inhibit debris mediated osteolysis. 5. Investigate the ability of statins to inhibit debris mediated osteolysis.;The study has been divided into a number of experiments. The first experiment was to demonstrate that cells from the interface membrane of aseptically loosened hips have the ability to resorb bone using the established radiolabelled murine calvaria model and at the same time to show that NTx can be used in this model as a resorption marker.;The second experiments involved the development of a new in vitro debris mediated osteolysis model using human bone instead of radiolabelled murine calvaria and again using NTx as the bone resorption marker.;The third and fourth experiments involved exploring the possibilities of doxycycline and statins for the potential treatment of aseptic loosening.