Anteromedial Gonarthrosis (AMG) is a distinct phenotype of knee osteoarthritis (OA), with a specific pattern of disease on the tibia. There is full thickness cartilage loss anteromedially, progressing to an area of damaged cartilage, and then to an area of macroscopically and histologically normal cartilage posteriorly. This reproducible pattern of disease can be considered to be a spatial model of OA progression and provides an alternative and less biologically varied set of specimens than the commonly used multiple joint compartments in which to quantify disease-related changes. The aim of this thesis was to explore in detail spatial and quantitative differences in cell, matrix and molecular features between areas of cartilage in AMG. A real time PCR study was undertaken comparing damaged and undamaged cartilage in AMG. Previous work from our research group had shown increased type I collagen content of undamaged cartilage in AMG. This gene expression study corroborated this finding by demonstrating increased COL1A1 expression in undamaged cartilage, compared to damaged cartilage. MMP1, MMP3, MMP13 and ADAMTS4 were also shown to have increased expression in undamaged cartilage. Since these changes arise in tissue before any macroscopic damage is apparent, these may indicate early changes of the cartilage matrix in AMG. In order to confirm that these changes are directly related to the damage process and not only to normal regional variations, Above Knee Amputations were collected from patients with peripheral vascular disease but no overt OA and a template of the AMG joint surface created to allow for matched regional sampling. Studies into their histology, immunoassays and qPCR were performed in order to compare results with those from AMG specimens. Histology demonstrated low scores throughout but allowed for a division into lower (macroscopically and histologically normal) and higher grade (surface wear/possible early signs of OA) groups. Immunoassays showed elevated type I collagen in high grade but not low grade groups in the posterior cartilage. No differences in mRNA expression were detected using qPCR suggesting that changes seen in AMG specimens were specific to the OA disease process. Because the causes of cell death in OA are not fully understood an immunohistochemical study into apoptosis was performed. TUNEL staining demonstrated higher levels of apoptosis, the more damaged the cartilage. The presence of Active Caspase 3, Cytochrome C, Active Bax and Bim with the same distributions demonstrated apoptosis occurring via the intrinsic or mitochondrial pathway. The high levels of 3-Nitrotyosine in more damaged cartilage implicated reactive oxygen species in apoptotic mechanisms. A microarray study was conducted comparing regions of damaged and undamaged cartilage in AMG. 389 genes were found to be significantly differentially expressed between regions. Several pathways rich in gene expression changes were highlighted including cellular development, inflammatory response and skeletal disorders. Results suggest complex changes in the signaling microenvironment of AMG and identify areas for future study. In summary, this thesis has highlighted several quantitative molecular and cellular differences between regions of cartilage in AMG, demonstrating its usefulness as a tight disease model. Gene expression differences corroborate changes previously seen by immunohistochemistry; microarray has shown the wider picture of gene expression changes. Apoptosis has been shown to occur via the intrinsic pathway and involve reactive oxygen species, highlighting this damage pathway as an important driver of cell loss. Most importantly this thesis has identified the apparently normal region in AMG specimens as a region undergoing considerable molecular changes and as a potential early disease model. The dysregulation of collagen I distribution seen in AMG and slightly worn AKA specimens is very interesting and suggests a possible early response to loading alterations caused by joint wear and opening the way for future experiments. The identification of wear patterns in AKA specimens specifically mapping to the zone of maximal damage in AMG confirms the site of initial injury and progression over time proposed in this model. These AKA specimens with no overt OA should therefore be used in future studies to assess emerging biomarkers of disease progression.

Anteromedial osteoarthritis of the knee (AMOA) has been defined anatomically, histologically and radiologically and yet little is known about the epidemiology of the disease or the risk factors involved in the development of the disease. The broad aim of this thesis was to combine clinical insight with the utilisation of modern, large epidemiological datasets to provide information to inform better the clinical management of patients with AMOA. Specifically, the prevalence and incidence of AMOA, the time taken to progress from early disease to severe disease that may require surgical intervention, the radiological characterisation of disease and the assessment of mechanical risk factors implicit in the development of this pattern of disease are investigated. A cross-sectional study of the radiological prevalence of AMOA in a symptomatic cohort in a specialist secondary care knee clinic showed that AMOA was the commonest pattern of knee OA, present in more than 60% of symptomatic subjects. Less than 25% of subjects with AMOA presented with advanced or 'bone-on-bone' disease, emphasising the clinical importance of understanding the progression from earlier stages of disease to this advanced stage. A 20-year longitudinal radiographic study was performed on 1000 women to describe the prevalence, incidence and progression of AMOA. The prevalence of AMOA was 43% and the incidence over 20-years was 0.4. Life table analysis showed that the risk of developing advanced AMOA in a previously normal knee was 2.6%. Of those subjects with early radiological AMOA, 11% progressed to advanced 'bone-on-bone' disease within 10 years and 37% within 20 years. The role of mechanical risk factors in the development of AMOA showed that both anatomical limb and proximal tibial alignment were significantly more varus aligned in those that developed AMOA at 20-years. Assessment of the shape of the medial tibial plateau in a longitudinal MRI study showed that the angle of the upslope at the anterior aspect of the plateau was significantly increased in the group that subsequently developed AMOA. To enable AMOA to be studies in future MRI studies, the MRI description of the disease was defined. In summary, AMOA was shown to be the most common pattern of knee OA both in symptomatic surgical cohorts and in the community. The progression of the disease from an early stage to an advanced stage, which may require surgical intervention, was described for the first time. To enable better the recognition of AMOA in modern epidemiological studies, the MRI description of AMOA was defined and the clinical relevance of modern MRI was discussed. The anatomical alignment of the limb, the alignment of the proximal tibia and the morphology of the tibial plateau were all shown to have a role in the development of AMOA. Addressing these mechanical factors may provide a therapeutic surgical target for the management of patients with AMOA.

Morbus​ ​Perthes​ ​(LCP)​ ​is​ ​an​ ​idiopathic​ ​defect​ ​in​ ​the​ ​blood​ ​flow​ ​of​ ​the​ ​proximal femoral​ ​epiphysis,​ ​where​ ​morphological​ ​and​ ​functional​ ​pathologies​ ​of​ ​the​ ​hip​ ​joint occur.​ ​Unfavorable​ ​prognostic​ ​factors​ ​include​ ​aspheric​ ​and​ ​incongruent​ ​hip,​ ​often manifested​ ​by​ ​the​ ​appearance​ ​of​ ​hinge​ ​abduction.​ ​The​ ​head​ ​is​ ​no​ ​longer​ ​remodeling after​ ​"golden"​ ​period​ ​of​ ​remodellation.​ ​Anteromedial​ ​Wedge​ ​Reduction​ ​Osteotomy (AWRO)​ ​is​ ​a​ ​new​ ​surgical​ ​method​ ​to​ ​improve​ ​the​ ​shape​ ​and​ ​reduce​ ​the​ ​femoral head​ ​and​ ​thus​ ​extend​ ​the​ ​life​ ​of​ ​a​ ​significantly​ ​altered​ ​hip​ ​joint. We​ ​evaluated​ ​10​ ​patients​ ​after​ ​the​ ​AWRO​ ​and​ ​established​ ​3​ ​hypotheses,​ ​in​ ​the clinical​ ​part​ ​of​ ​the​ ​study.​ ​1st​ ​hypothesis​ ​"AWRO​ ​leads​ ​to​ ​the​ ​reshape​ ​of​ ​the​ ​head" was​ ​confirmed​ ​following​ ​the​ ​Stulberg's​ ​classification.​ ​2nd​ ​hypothesis​ ​"AWRO​ ​leads to​ ​a​ ​reduction​ ​in​ ​the​ ​mediolateral​ ​diameter​ ​of​ ​the​ ​head",​ ​was​ ​confirmed​ ​by​ ​measuring the​ ​capitodiaphyseal​ ​index,​ ​which​ ​was​ ​reduced​ ​in​ ​all​ ​femoral​ ​heads​ ​after​ ​AWRO. The​ ​3rd​ ​hypothesis​ ​"Harris​ ​Hip​ ​Score​ ​improved​ ​in​ ​medium-term​ ​follow​ ​up​...