Osteoarthritis (OA) is the most common type of arthritis worldwide and a significant cause of pain and disability. Modem imaging, in particular magnetic resonance imaging (MRI), has revolutionized the understanding of this disease and it is now known that OA affects the whole joint in a dynamic, remodelling process. Current treatments for OA, such as anti-inflammatory drugs, analgesics or corticosteroid injections only have, at best, a moderate effect size and their use may be limited by side-effects. Recent modem imaging studies have identified the synovium as a target for treatment as inflammation in the synovium has been associated with pain. This thesis assessed whether targeting the synovium with anti-synovial agents would improve clinical symptoms in OA and whether differing imaging modalities would improve the synovitis- symptom relationship. An open label study of methotrexate demonstrated analgesic efficacy in OA of the knee and a randomised controlled trial is suggested. All participants had ultrasound- detected synovitis at baseline but there was no association between imaging and clinical features. A randomised controlled trial of low dose oral prednisolone for treating painful hand OA did not demonstrate any benefit above placebo. Extremity MRI found no clear associations between baseline imaging and clinical symptoms, although a finger joint that had definite synovitis or effusion on imaging was more likely to be painful, or swollen, or tender. Lastly, MRI was used to assess changes in the synovium after intra-articular corticosteroid. A reduction in synovitis was demonstrated using both synovial volumetric analysis and a semi- quantitative score. Dynamic MRI was able to demonstrate changes in the early enhancement rate, late static enhancement and a statistically significant reduction in the novel variable total synovial enhancement. Synovial volumetric analysis and some dynamic variables were associated with pain scores at baseline. Dynamic MRI shows potential as a more sensitive outcome measure in OA clinical studies, which may improve the synovium-syrnptorn relationship.

Multiple epiphyseal dysplasia (MED) is characterized by dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the precise disease mechanisms that underpin the pathophysiology of MED, a knock-in murine model of MED has recently been generated with the disease-causing matn3: V194D mutation. Mice that are homozygous for the mutation (MM) are normal at birth but develop a progressive dysplasia that is characterized by the intracellular retention of mutant matrilin-3. The mutant mice also display a significant decrease in chondrocyte proliferation and dysregulated apoptosis by 3 weeks of age.

<p class=MsoNormal>This study determined the response of elderly human articular cartilage explants to static, cyclic or absence of mechanical load, with or without the addition of the maintenance factor IGF-1.  It revealed that elderly human articular cartilage does not behave in the same way as young animal tissue, with cyclic and static loading both causing an inhibition in matrix biosynthesis.  In addition, cyclic mechanical load appears to block the effects of IGF-1 in elderly human tissue, in contrast to bovine tissue in which the effects were additive.  Osteoarthritic bone was found to have double the fat content of osteoporotic bone and, within the fatty acid profile, arachidonic acid was present at twice the concentration.  Surprisingly, the addition of arachidonic acid to cartilage explants appeared to have no effect on matrix biosynthesis though, in retrospect, this may have been a methodological problem. <p class=MsoNormal>A pilot study using gene arrays revealed factors previously unidentified which may be crucial to the mechanotransduction process in chondrocytes.  The considerable upregulation of transcripts for anabolic factors with no corresponding upregulation of those for matrix macromolecules raises questions about how mechanical processes regulate genes. In summary, this thesis has demonstrated that mechanical and chemokine factors interact in ways different to those found in animal cartilage.  The role of fatty acids in mature human cartilage requires further investigation, but mechanically stimulated transcription of genes for anabolic factors does not appear to result in increased matrix synthesis.

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Background. Knee osteoarthritis (OA) can result in considerable pain and disability for some people. Inflammation within the joint may be partly responsible for the pain associated with OA and a link between inflammation and disease progression has been suggested. Ultrasound (US) imaging has been successfully employed in the evaluation of knee joint effusion, synovial hypertrophy and power doppler signal (PDS) which are said to represent joint inflammation. The associations between US features of inflammation, knee pain and radiographic OA have yet to be firmly established. Objectives. The objectives of this thesis were to compare the frequency of US features of inflammation in 4 groups from a community sample, [1] those with normal knees (controls) [2] knee pain - without radiographic OA (KP) [3] radiographic OA (without pain) (ROA) and [4] symptomatic OA (SOA). Associations between US features, knee pain, radiographic change and clinical signs of inflammation could then be explored. Secondary objectives were to determine if US features change in tandem with fluctuations in knee pain (1) over time and (2) with improved pain following a therapeutic intervention in people with SOA. Methods. In a cross-sectional multiple group comparison study, 243 participants were divided into 4 groups based on the presence of absence of knee pain and ROA. All underwent an US examination for effusion, synovial hypertrophy, peri-articular cysts and PDS. The presence or absence of features, absolute measures (millimetres) and grade of PDS (0-3) was recorded for both knees. Radiographs and clinical evaluation of knee pain, biomechanical stiffness and function were also undertaken. Follow-up examination of control and SOA groups was undertaken at 3 months. Participants with SOA were then invited to take part in a randomised placebo-controlled study of intra-articular (IA) cortico-steroid and a saline placebo. Results. The frequency of US features in the control group (effusions (29%) synovial hypertrophy (8%), popliteal cysts (12%) and PD signal (2%)) was not significantly different from those in the KP group. US features were more common in ROA and higher again in SOA (effusion 81% and 92% respectively, synovial hypertrophy 41% and 82%, popliteal cysts 22% and 39%). PDS was not significantly different between ROA (6.3%) and SOA (16%). Synovial hypertrophy was the only US feature independently associated with knee pain after adjusting for ROA (aOR 6.6; 95% CI 2.85, 15.11). All grey-scale features were strongly associated with ROA and remained so after adjusting for pain (effusion aOR 13.39, 95%CI 6.14, 29.02; synovial hypertrophy aOR 14.39, 95%CI 6.28, 32.94; popliteal cysts aOR 2.82, 95%CI 0.76, 10.43). PDS was not association with either knee pain or radiographic OA. Change in pain severity was not found to correlate with and change in US measures among the participants followed up at 3 months or following improved pain among participants in the intervention study. Conclusion. These findings show that US features suggestive of inflammation are higher in participants with SOA but was only significant for synovial hypertrophy. Synovial hypertrophy was confirmed as an independent risk factor for knee pain but was not found to be responsive to temporal changes in pain or improved pain following an IA cortico-steroid or placebo injection. Further studies to understand the contribution of US features of inflammation to pain in knee OA are warranted.

Osteoarthritis (OA), depression and anxiety are common problems in primary care. OA coexisting with depressive and/or anxiety symptoms has detrimental consequences to the individual. To inform recognition and management of these important problems in primary care a better understanding of their coexistence is needed. A systematic review with meta-analysis was undertaken to determine the prevalence of depression and anxiety in adults with OA/joint pain in the community. Elevated anxiety symptoms were more common (45%) than depression symptoms (24%) in persons with OA joint pain. Sources of between study variance include methods of ascertainment and geographical location. A review of measurement properties of several recommended patient-reported depression and anxiety measures found evidence to support properties in some populations, but some critical properties warrant investigation in adults with OA in the community. A secondary data analysis was conducted for older consecutive primary care patients with musculoskeletal pain recruited to a cohort (n=443) of the PROGnostic Research study. Latent Class Growth Analyses identified clusters of individuals who exhibited different trajectories of anxiety and depression symptoms over a 12-month period: three anxiety and two depression symptom trajectories. In total, 56% and 63% of participants experienced persistent anxiety and depression symptoms respectively for at least 12 months. Pain characteristics and coping strategies were the most prominent risk factors for persistent anxiety and depression symptoms. With the aim of identifying individuals with sub- threshold persistent anxiety and depression symptoms, characteristics predisposing to symptoms persistence may be considered. A medical records review found that only half of all older musculoskeletal patients with persistent anxiety and depression symptoms have their mental health problems detected by their GP. Frequent consulters and those with more severe anxiety were more likely to be detected. This reinforces the need to recognise and manage OA coexisting with depression and/or anxiety by patients and health professionals alike.

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Medial osteoarthritis (OA) and lateral OA have distinct characteristic cartilage lesion locations and knee flexion angles associated with lesion development. These types of OA are suggested to be caused by loading when the knee is in extension and mid-range flexion, respectively. This project used subject-specific finite element (FE) models to investigate contact conditions within the extended and flexed knee. A method of creating subject-specific FE models by combining geometry (derived from magnetic resonance imaging scans) and load cases (calculated from motion analysis data) collected from the same subject was developed. This model creation method was validated by comparing experimentally-measured pressure data to contact data calculated by FE models. Models of normal knees in three subjects were created first. Models with larger subject-specific loads had larger displacements and higher stresses and contact pressures. Contact occurred over most of the articulating cartilage surfaces, both in areas of typical cartilage lesions and outside areas of typical cartilage lesions. Parameters in the normal models were then altered to reflect three mechanical changes hypothesized to lead to OA: increased loading, globally decreased cartilage stiffness, and locally decreased cartilage stiffness. Increased loading led to increased displacements, stresses, and contact pressures. Contact shifted anteriorly in the extended knee models to locations of typical medial OA cartilage lesions; contact remained stationary with elevated stress magnitudes in the flexed knee models. Globally decreasing cartilage stiffness had limited effects on contact results. Locally decreased cartilage stiffness led to locally increased displacement and strain and locally decreased stress and contact pressure. Contact again shifted anteriorly in the extended knee models. Potential mechanisms of OA initiation were then proposed. Increased weight or locally decreased cartilage stiffness increased strains within the cartilage. High strains can damage the cartilage matrix fibres, further decreasing cartilage stiffness and eventually leading to cartilage lesions and OA.