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Accelerated osteoclastic bone resorption plays an important role in the pathogenesis of osteoporosis and other common bone diseases such as Paget's disease of bone, rheumatoid arthritis and cancer-associated bone disease. The prevention and treatment of these diseases is based on agents that inhibit osteoclast (OC) formation and resorption. Nitrated non-steroidal anti-flammatory drugs (NO-NSAID) are a recently developed group of compounds that contain a conventional NSAID linked to a nitric oxide (NO)-donor group. As prostaglandins and NO can both stimulate and inhibit OC formation and bone resorption, I investigated whether NO-NSAD may affect the bone loss observed in bone diseases. Both Flurbiprofen and its nitrated derivative NO-Flurbiprofen (HCT1026) inhibit IL-1-stimulated OC formation and resorption in mouse co-cultures. However, HCT1026 was much more potent than the parent compound Flurbiprofen. As resorption was completely blocked by HCT1026 even though there were still OC present, I studied the effect of this drug on actin ring formation as an indicator of OC activity HCT1026 significantly decreased the percentage of active OC within 4 hours and all actin rings had disappeared after 24 hours, whereas Flurbiprofen had no effects. HCT1027, a HCT1026 derivative that lacks the NO-donor properties, was a potent inhibitor of OC formation and resorption in both murine and human cultures. The fact that HCT1027 and HCT1026 were equipotent clearly demonstrates that the anti-resorptive effects of these compounds are not dependent on NO-donor properties. Both HCT1026 and HCT1027 were potent inducers of apoptosis in OC and J774 cells as evidenced by numbers of apoptotic nuclei and caspase-3 activation. Treatment of primary osteoblasts (OB) with HCT1026 for up to 72 hours failed to induce OB apoptosis, suggesting that this compound acts only on cells of the monocyte-macrophage lineage such as macrophages and OC. Intraperitoneal injection with ABD56 (10 mg/kg/day) completely prevented ovariectomy-induced bone loss in mice and maintained BMD at level comparable to those of non-ovariectomised Sham controls. Histomorphometrical analysis of the proximal tibial metaphysis indicated that ABD56 totally recovered ovariectomy-induced trabecular bone loss and significantly decreased OC number in both Sham- and ovariectomy-operated mice, whereas it had not significant effects on OB numbers. In conclusion, we successfully developed a novel class of anti-resorptive drugs using structure-based drug design. The non-nitrated biphenyl carboxylic acid derivatives ABD56 and ABD68 are presented here as anti-resorptive agents that inhibit osteoclast formation, survival and resorption by a mechanism that is independent of NO production, COX inhibition and formation of metabolites. ABD56 prevents ovariectomy-induced bone loss and induces apoptosis in mature OC in vitro by inhibiting NFkB and p42/44 activity. Although its exact mechanism of action is yet unclear, ABD56 is a promising therapeutic candidate for the treatment of bone diseases associated with accelerated bone loss due to osteoclast activation such as osteoporosis, RA and cancer associated bone disease.

Ellis-van Creveld (EvC) syndrome is an autosomal recessive skeletal dysplasia characterised by shortening of long bones and polydactyly. Professor Goodship's research group had previously identified the cause of EvC as mutations in two novel genes called EVC and EVCI. They developed an Evc knockout mouse which exhibits an EvC-like phenotype. Evc localizes at the base of fibroblast primary cilia which are essential for hedgehog signalling. Hedgehog pathway defects can cause similar abnormalities to those seen in EvC.

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Advances in our understanding of human locomotion can be futile if no practical use is made of them. For the long-term benefit of patients in a clinical setting, scientists and engineers need to forge stronger links with orthopaedic surgeons to make the most use of the recent developments in motion analysis technology. With this requirement as a driving-force, an objective classification tool was developed that uses motion analysis for an application to clinical diagnostics and monitoring, namely knee osteoarthritis (OA) progression and total knee replacement (TKR) recovery. The classification tool is based around the Dempster-Shafer (DS) theory, and as such is built upon the sound foundations of Bayesian statistics. The tool expands on the work of Safranek et al. (1990) and Gerig et al. (2000) who developed and used parts of the classification method in the areas of vision and medical image analysis respectively. Using the data collected during a clinical knee trial, this novel approach enables the objective classification of subjects into an OA or normal group. Each piece of data is transformed into a set of belief values: a level of belief that a subject has OA knee function, a level of belief that a subject has NL knee function and an associated level of uncertainty. The belief values are then represented on a simplex plot, which enables the final classification of a subject, and the level of benefit achieved by TKR surgery to be visualised. The DS method can be used as a fully or partially automated tool. The input variables and control parameters, which are an intrinsic part of the tool, can be chosen by an expert or an optimisation approach. Using a leave-one-out (LOO) approach, the tool was able to classify new subjects with an accuracy of 97.62%. This compares with the 63.89% and 95.24% LOO accuracies of two well-established methods---the Artificial Neural Network and the Linear Discriminant Analysis classifiers respectively. The tool also provides an objective indication of the variables that are the most influential in distinguishing OA and NL knee function. In this case, the variables identified by the tool as important are often cited as clinically relevant variables, which enhances the appeal of the tool to the clinical community and allows for more effective comparison with clinical approaches to diagnosis. Using Simulated Annealing to select the control parameters reduced the LOO accuracy to 95.24%. Automated feature selection using a Genetic Algorithm and Sequential Forward Selection increased the LOO accuracy to 100%. However, further work is required to improve the effect of this process on the overall level of uncertainty in the classification. Initial studies have demonstrated a practical and visual approach that can discriminate between the characteristics of NL and OA knee function with a high level of accuracy. Further development will enable the tool to assist orthopaedic surgeons and therapists in making clinical decisions, and thus promote increased confidence in a patient's medical care.

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Bone ensures it is sufficiently robust to withstand habitual levels of mechanical loading without unsustainable levels of damage by adapting to the strain environment engendered by normal activity. This process becomes less effective with age when loss of bone tissue occurs despite continued activity. Here I report experiments to investigate the (re)modelling response to a loading challenge in both trabecular and cortical bone in young adult and aged male and female mice against different levels of background activity. Loading-related increases in trabecular and cortical bone in response to short periods of unilateral non-invasive axial loading of the tibia were compared between young and aged male and female mice. In trabecular bone, increase in connectivity was impaired with age. In cortical bone the increase in new bone formation was less and endosteal instead of periosteal. Remarkably both the size and location of this response in the cortices of aged animals could be “rescued” by inducing disuse in the same limb by sciatic neurectomy. Conversely, concurrent treadmill exercise, while having potentially beneficial systemic effects, did not enhance the adaptive response to loading. Studies aimed at identifying the stage of the adaptive response to loading where aged animals first digressed from young adults showed that strain-related sclerostin down regulation, which occurs in osteocytes 12-24 hours after loading, was unaffected by age. However, ageing was associated with a lower increase in active periosteal osteoblasts. In vitro, primary osteoblast-like cells derived from long bones of young and aged mice showed age-related sex-specific alterations in their responses to strain 1 hour following strain. In cells from aged female mice, a cell cycle arrest during proliferation was observed 24 hours after strain. Microarray analysis of tibiae in vivo showed that over 150 genes regulating the cell cycle were altered with age.