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Ashraf, Sadaf (2011)
Languages: English
Types: Unknown
Background: Osteoarthritis (OA), one of the commonest joint diseases of unknown aetiology is a major source of pain and disability in the ageing population. Current therapeutic agents for OA focus on symptomatic relief. Patients often present to clinics with long established disease when the boundaries between ageing and pathology are indistinct. A greater understanding of early OA is thus required and may help achieve the goal of disease modification. OA is associated with chondropathy, synovitis, subchondral bone remodelling and osteophyte formation. Angiogenesis, the growth of new blood vessels from pre-existing ones may contribute to each of these features. Inflammation is increasingly recognised as an important feature of OA. Synovitis is detectable within the osteoarthritic joint both radiologically and histologically, evidenced by symptoms such as stiffness or pain, signs such as effusion and use of anti-inflammatory drugs for treatment of OA. Pain is the predominant symptom of OA, but little is known about the mechanism by which this pain arises. Objectives: This thesis describes studies examining the contributions of angiogenesis to inflammation, structural damage and pain in OA. Hypothesis: Inflammation and angiogenesis are co-dependent processes that can exacerbate and mediate structural damage and pain in OA. Methods: In-vivo, in animal models and ex-vivo in human meniscal tissue, using immunohistochemistry, joint histology and pain behaviour testing, the effects of enhancing synovitis on angiogenesis, structural damage and pain in OA, and whether inhibiting either synovitis or angiogenesis could reduce this structural damage and pain were investigated. Results: It is shown for the first time that blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence. Exacerbating synovitis in the rat meniscal transection (MNX) model of OA enhanced synovial angiogenesis, total joint damage and pain behaviour. Following treatment with the anti-angiogenic compound, PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R, 3S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl) oxiranyl]-1-oxaspiro (2*5) oct-6-yl ester], synovial angiogenesis, vascularisation of channels penetrating into the articular cartilage (osteochondral angiogenesis), synovitis, joint damage (mainly attenuation of osteophyte growth) and pain behaviour were all reduced. Anti-inflammatory drugs (dexamethasone and indomethacin) reduced synovitis, synovial angiogenesis and pain behaviour in the rat MNX model of OA. Treatment with dexamethasone reduced joint damage score by decreasing cartilage damage. Indomethacin however did not affect joint structure. Human meniscal tissue from knees with high chondropathy displayed increased degeneration of collagen bundles, increased vascular densities both in the synovium and at the fibrocartilage junction with a greater density of perivascular sensory nerve profiles in the outer region. Increased penetration of the synovial tissue towards the tip of the meniscus was noted in menisci from high chondropathy group compared to those from the low chondropathy group. Conclusion: Data from animal studies indicates that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis. Furthermore, these data provide evidence that synovitis contributes to joint pathology and pain behaviour in the rat MNX model of OA and this may be partly due to the angiogenesis in the synovium and at the osteochondral junction. Data from human studies highlights that tibiofemoral chondropathy is associated with altered matrix structure, increased vascular penetration and increased sensory nerve densities in the medial meniscus. Angiogenesis and associated sensory nerves in the meniscus may therefore contribute to pain in knee OA. Summary: These findings support the hypothesis that inflammation and angiogenesis are indeed co-dependent processes, exacerbating and mediating structural damage and pain in OA. Angiogenesis inhibition has the potential to reduce synovitis, joint damage and pain in OA.
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    • 1.8 Animal Models of Osteoarthritis
    • 1.9 Summary
    • 1.10 Hypothesis and Aims
    • 2.1 Introduction
    • 2.2 Animal Models 2.2.1 Anaesthesia 2.2.2 Euthanasia 2.2.3 Intra-articular injection into rat knee joints 2.2.4 Subcutaneous Injections 2.2.5 Oral Gavage 2.2.6 Meniscal Transection (MNX) Model of Osteoarthritis 2.3 Behavioural Testing 2.3.1 Pain Testing 2.3.2 Weights
    • 2.4 Joint Swelling
    • 2.5 Tissue Collection and Processing 2.5.1 Harvesting and Mounting Rat Synovia 2.5.2 Harvesting and Mounting Rat Tibiofemoral Joints 2.5.3 Human Menisci 2.5.4 Systemic Transcardiac Perfusion of Rat Tibiofemoral Joints 2.5.5 Blood Glucose Testing
    • 2.6 Immunohistochemistry 2.6.1 Introduction 2.6.2 Principles Involved 2.6.3 Staining Procedures
    • 2.7 Histological Stains 2.7.1 Haematoxylin and Eosin 2.7.2 Safranin-O and fast green
    • 2.8 Image Analysis and Quantification 2.8.1 Synovia 2.8.2 Cartilage and Subchondral Bone 2.8.3 Human Menisci
    • 2.9 Patient and Sample Selection for Human Menisci Study 2.9.1 Macroscopic Chondropathy Score of Tibiofemoral Joint 2.10 Statistical Analysis
    • 2.11 Reagents
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