Abstract
Chronic joint disorders are a major cause of impaired mobility and loss of quality of life in both humans and horses. Regardless of the primary insult, any joint disorder is characterized by an upset in normal joint homeostasis, the balance between tissue anabolism and catabolism that is normally maintained by resident articular cells. This upset is often fuelled by a local inflammatory response in the synovial membrane and the articular cartilage. Our current understanding of the pathogenesis of chronic joint disease is hampered by a lack of tools for the accurate assessment of joint homeostasis. This thesis explores the analysis of direct (cartilage components) and indirect biomarkers (paracrine effectors like cytokines, inflammatory mediators and catabolic enzymes) in synovial fluid from horses with naturally occurring and experimentally induced disease as a means to study real-time changes in the intra-articular environment. Clinical investigations in joints with osteochondrosis and early osteoarthritis identified differences in cartilage turnover and growth factor concentrations in young foals, but not older horses, with osteochondrosis compared to age-matched control animals, while cartilage markers did not differ between lame horses with and without clinically detectable joint pain. Importantly however, all clinically active joints were characterized by a significant level of ongoing inflammation, even in conditions like osteochondrosis that are not usually considered inflammatory in nature. Synovial inflammation was evidenced by elevated concentrations of specific local mediators like substance P in painful joints, prostaglandin E2 in lame horses and leukotriene B4 and prostaglandin E2 in horses with clinical osteochondrosis. Cross-sectional studies of natural disease are marred by numerous confounding factors that may obscure relations between marker concentrations and disease status. To investigate the impact of primary inflammation on in vivo cartilage turnover and to study the time course of early inflammatory and degradative events within the joint space, a longitudinal experimental approach was adopted. Fully reversible acute synovitis was induced in joints of healthy horses by injection of 0.5 nanogram lipopolysaccharide (LPS) and synovial fluid biomarkers were monitored over the course of the local inflammatory response. By adopting a cross-over design for these studies, longitudinal monitoring of synovial fluid marker markers could simultaneously be used for the in vivo evaluation of effects of commonly used therapeutics (oral administration of an NSAID and intra-articular injection of morphine) within the joint space, compared to placebo treatment. These studies showed that inflammatory mediator and cytokine release (bradykinin, substance P, prostaglandins, HETEs, HMGB-1) as well as Matrix Metalloproteinase activity rose rapidly after the onset of inflammation. Also, both anabolic and catabolic markers of proteoglycan and type II collagen, each with their own time course, peaked in response to primary joint inflammation. Oral administration of an NSAID proved to reduce a host of lipid and peptide synovial inflammatory mediators, but also to limit the inflammation-induced rises in MMP activity and cartilage turnover markers, while morphine showed local anti-inflammatory effects but did not reduce the accompanying peaks in cartilage turnover markers. Altogether, this work demonstrates the potential for synovial fluid biomarkers as relatively non-invasive research tools and surrogate outcome measures for in vivo monitoring of effects of novel or existing therapeutic interventions for the treatment of joint disease
Original language | English |
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Qualification | Doctor of Philosophy |
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Award date | 10 Dec 2010 |
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Print ISBNs | 978-90-393-5419-3 |
Publication status | Published - 10 Dec 2010 |