Osteoarthritis (OA) is characterized by pain, and problems with activities of daily life, especially if the hip or knee joint is affected. The aim of this project was to study associations between strength, voluntary activation and functioning in elderly patients with OA. People with OA of the knee often have lower muscle strength, but also a lower ability to voluntarily activate their knee extensors. In Chapter 2 we investigated the effects of relatively low stimulation currents on the assessment of VA of the knee extensor muscles. We concluded that by using submaximal muscle stimulation overestimation of VA may even be less compared with maximal nerve stimulation. In Chapter 3, we investigated physical performance longitudinally in a large cohort of participants with and without self-reported hip or knee OA. Physical performance was tested with a short battery consisting of a chair stand test, a balance test and a 6 meter walk test, performed in the participants' home. Chair stand and walking performance were lower in participants with OA 3 to 6 years after OA was reported for the first time, and men were more affected than women. In the laboratory, more elaborate lab tests can be done, such as strength testing, standardized stair climb tests and longer walk tests. Such lab tests may be more sensitive to detect impairments. In Chapter 4, we compared home tests used in Chapter 3 with a set of frequently used lab tests to investigate whether home tests are indeed a good alternative if time and space are limited. Also we investigated differences in functioning in a sample of participants with and without knee OA. Home tests were significantly related to lab tests and showed reasonable relationships. Only the battery of home tests showed lower performance in participants with OA. In Chapter 5, we investigated the feasibility and effectiveness of 6 weeks of preoperative training for elderly OA patients undergoing total knee arthroplasty. Pre and post operative outcome measures were not different compared to a standard training group. We conclude that physical function, but not VA is impaired in older people with OA and that strength and physical function is more impaired just before total knee arthroplasty. When assessing function in older participants or patients with musculoskeletal disorders, home tests are a good alternative to lab tests to obtain a representative sample. Preoperative training before total knee arthroplasty can prevent the decline in function often observed before surgery, but there were no additional effects of intensive strength training.

No description available.

Obesity is strongly associated with knee osteoarthritis (OA), and weight loss has been implicated in reducing the progression of the disease. The initiation and progression of OA cartilage lesions and osteophyte formation in the Dunkin Hartley (DH) guinea pig model of OA have been well characterised, and many features parallel findings in human OA tissue. However, the role of the bone, including subchondral and metaphysical bone in obesity-mediated OA progression has not been defined. Dietary restriction (DR) was used to reduce weight gain, and the effects on OA progression, bone metabolism, bone quality and gene expression were investigated in DH guinea pigs. Cartilage lesion formation was determined using macroscopic analysis. Changes in bone mass were characterised by measurement of the tibial plateau dimensions, pQCT and histomorphometry. These data were further confirmed by assessing the levels of urinary and serum biomarkers of bone turnover. Microarray technology was utilised to asses the effects of DR on the expression of genes involved in OA and/or bone function and regulation. Attempts were made to validate the expression of genes from these experiments by TaqMan(TM) PCR and immunodetection. Dietary restriction reduced bodyweight, cartilage lesion severity and bone turnover, but increased osteophyte formation. Microarray was performed but due to a number of issues, including validation, these data must be treated with caution. Overall, DR was found to prevent the progression of knee OA and OA-induced changes in bone metabolism, many features of which support findings from human OA studies.

Osteoarthritis (OA) is the most common form of joint disease and a leading cause of physical disability woridwide. Cartilage degradation in OA is due to an imbalance between synthesis and degradation of the extracellular matrix. Recent work from our laboratory has shown that the heparin-binding growth factor fibroblast growth factor2 (FGF-2) mediates key responses in cartilage following mechanical trauma and loading. It has also been shown that FGF-2 is localised within the pericellular matrix, attached to the heparan sulphate proteoglycan perlecan. The spatial modulator of chondrocyte function. The primary aim of this research was to define the role of FGF-2 in cartilage degradation in vivo. Mice with deletion of Fgf2, whilst morphologically indistinguishable from wild-type animals, exhibited accelerated spontaneous and surgically-induced OA. Surgically-induced OA in Fgf2 mice was suppressed to wild type levels by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2 mice was associated with increased expression of ADAMTS-5, the key murine aggrecanase, but not other matrix metalloproteinases. Explants from Fgf2 mice showed increased aggrecanolysis and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motif, type 5; aggrecanase-2) gene expression following interleukin-1 (IL-1) stimulation, and exogenous FGF-2 suppressed IL-1 induced aggrecanolysis in wild-type explants. These data identify FGF-2 as a novel endogenous chondroprotective agent, and as an inhibitor of aggrecan breakdown acting through suppression of ADAMTS-5.

Background: Knee osteoarthrit is (OA) is one of the leading musculoskeletal burdens in the world, causing both structural damage and pain to the joint. Radiographs are the most common imaging method for diagnosing OA, however the relationship between radiographic changes (ROA) and symptoms is not well understood. This thesis will establish the natura l history of twenty-year ROA, compare diagnostic methods of ROA assessment, evaluate the cross-sectional relationship between ROA and pain, and will determine the long-term predictive validity of features of ROA with future knee rep lacements. Methods: Data from the Chingford women's study, a twenty-year prospective UK-based cohort was used for the analysis. Risk factors included atlas-based ROA scoring methods and quantitative joint space width, which were analysed against pain and TKR outcome measures. A novel method for assessing joint space on low-contrast x-rays was developed which had high reproducibility and validity. ii

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 COLlAI expression in undamaged cartilage, compared to damaged cartilage. MMPl, 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 col1!lgen 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

No description available.

Purpose: Variation in morphology in the proximal femur and pelvis (e.g. acetabular dysplasia, non-spherical femoral head) can biomechanically compromise the hip joint and predispose to hip osteoarthritis (OA). Such morphological variation may in part explain the heritability of hip OA. The objective of this study was to evaluate a range of 2-dimensional morphological measures on standard radiographs to determine: normal range, right: left symmetry, age and gender differences; and to investigate whether they are associated with the risk of hip OA. Methods: A nested case control study was undertaken in 566 unilateral hip OA cases and 1108 controls in the established Nottingham Genetics of Osteoarthritis and Lifestyle (GOAL) database. Unaffected hips of unilateral hip OA cases were compared to the normal controls, under the assumption that similar morphological features would be observed for the affected hips prior to the development of hip OA. Definition of radiographic hip OA was joint space width (JSW) ~ 2.5 mm. Standardized antero-posterior (AP) radiographs of the pelvis were used to measure the morphological features. Measurements were performed by a single observer and the reproducibility was evaluated at baseline, mid and end of the study. Normal values, thresholds (mean±1.96SD) and symmetry of the features were derived from the control subjects. The intra-observer reliability was examined using intra-class correlation coefficient (ICC). Odds ratio (OR) and 95% confidence interval (Cl) were calculated for association. Logistic regression was used to adjust for age, gender and body mass index (BM!). Measurements were divided into tertiles to examine dose response. ii Results: The intra-observer reliability

Age is the most important risk factor in the development of osteoarthritis (OA). Numerous studies have now demonstrated that age-related changes occur in both the extracellular matrix and chondrocytes of OA cartilage and such changes are proposed to alter the tissue's biomechanical properties, thus predisposing to OA onset. The study presented here describes further investigation of two such age-related changes, cellular senescence and oxidative stress.

Recent advances in medical technology have revealed osteoarthritis to be truly multifactorial, affecting all the major tissues in synovial joints. Despite these advances and the fact that osteoarthritis is the most prevalent joint disease worldwide, our grasp of its etiology and underlying pathological process is still remarkably poor. Subchondral bone pathology in osteoarthritis is one area in particular that has been neglected. Thus, investigators must focus on defining the processes that control the causation and repair mechanisms in osteoarthritis before a viable therapeutic target is identified. In vitro investigations have relied on animal models in osteoarthritis research; however the degree to which they reflect human properties differs and their validity remains in question. The overall aim of this thesis was to develop a greater understanding of the osteoarthritis disease process and characterise the tibiofemoral osteochondral properties of three quadrupeds, to improve in vitro osteoarthritis research. A novel fully quantitative methodology was utilised to characterise the natural history of bone marrow lesions, a form of trabecular bone disruption, in subjects with knee osteoarthritis. Using a combination of manual image segmentation and automated statistical bone shape modelling the spatial distribution and volumetric change over a 24 month period was investigated. Furthermore, cartilage segmentations were incorporated to determine whether bone marrow lesions correlated with osteochondral progression in osteoarthritis. Results revealed the lesions to be inherently unstable and prevalent in subjects with knee osteoarthritis. The spatial distribution and significant association to deleterious joint loading environment suggested a mechanical role in bone marrow lesion genesis. Worsening cartilage pathology was significantly associated with increased bone marrow lesion volume and a striking co-location between trabecular disruption and cartilage denudation was identified. These findings identified a clear need for further investigations focussed on the role of trabecular bone changes in osteoarthritis. In vitro analysis was targeted as a potential forum for these studies . - vi- Animals slaughtered for human consumption are routinely used in vitro for musculoskeletal studies. Unfortunately little data has been published validating model selection. A series of imaging and mechanical testing techniques were used to characterise variation in the osteochondral properties of porcine, bovine and ovine stifle joints. Significant interspecies variation in animal maturity and osteochondral morphological and mechanical properties were identified. Results indicated none of the quadrupeds provided an ideal whole joint model for the human knee; but careful selection based on empirical evidence and study goals could be justified. In conclusion, more must be done to investigate how trabecular disruption affects the osteoarthritis pathological pathway, particularly in articular cartilage. In vitro analysis offers a controlled environment to perform these investigations; however access to human cadaveric tissue is notoriously challenging. In vitro quadruped animal models offer an alternative tissue source; however species selection must be validated based on tissue properties, and the inherent limitations of the model must be recognised.