Doctoral Degrees (Physiological Sciences)
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Browsing Doctoral Degrees (Physiological Sciences) by browse.metadata.advisor "Myburgh, Kathryn H"
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- ItemIntercellular communication between macrophages, myoblasts and fibroblasts in the context of rheumatoid arthritis-associated skeletal muscle wasting(Stellenbosch : Stellenbosch University, 2022-04) Ollewagen, Tracey; Smith, Carine; Myburgh, Kathryn H; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.ENGLISH ABSTRACT: Approximately 1% of the global population is afflicted with rheumatoid arthritis (RA), of which over a third experience rheumatoid cachexia, a RA-specific form of skeletal muscle wasting. Current patient research is focused on structural and functional outcomes of rheumatoid cachexia, with limited research focusing on the mechanisms causing this disease and their potential modulation. One of the most vital components to address are the complex cellular interactions occurring within the muscle, and how these interactions are affected by the chronic inflammatory autoimmune disease that is RA. To elucidate these mechanisms further, multiple models were used in this dissertation. Firstly, a rodent collagen-induced arthritis (CIA) model was used to represent RA. The aims of the first two rodent studies were as follows: (1) to determine the extent of ultrastructural change occurring in multiple muscle types as a result of the inflammatory condition; and (2) to assess different cell types, cytokines and growth factors and their relationships to muscle fibre size and number. Secondly, a novel triple cell (myoblast, fibroblast, macrophage) co-culture model was developed from primary human cell isolates, to mimic rheumatoid cachexia with the use of serum derived from RA and healthy participants. This study aimed to elucidate cellular responses to patient serum, as well as determine the efficacy of bone morphogenetic protein-7 (BMP-7) as a treatment strategy. The CIA model was a physiologically relevant and accurate model with which to investigate rheumatoid cachexia; several muscle types exhibited reductions in mass and cross-sectional area, in line with clinical reports. Furthermore, increases in fibrosis was reported in all muscle groups, independent of fibre type category. Furthermore, this model allowed for better understanding into the mechanisms of rheumatoid cachexia, with the persistent inflammation in the skeletal muscle contributing to heightened activation – but dysregulation – of muscle regenerative responses, resulting in inability to maintain the fibre size. Using this cellular profile of arthritis, the triple co-culture model was designed to allow for a human simulation of cellular signalling of co-cultured human primary cells in response to exposure to serum collected from non-RA controls and RA patients. iii Firstly, confirming accurate representation of disease signalling in control and patient serum, RA patient plasma indeed indicated dysregulated IL-6/IL-10 concentrations and a relatively pro-inflammatory state when compared to controls. Assessment of myoblast-, fibroblast- and macrophage-related parameters in the triple co-culture model demonstrated both dysregulated muscle and extracellular matrix formation in response to the treatment non-responding serum. These disease-associated outcomes were corrected/limited in the presence of BMP-7, suggesting a potential beneficial role for BMP-7 in management of rheumatoid cachexia. In conclusion, this dissertation significantly contributes to our understanding of rheumatoid cachexia by consistently illustrating, across in vitro and in vivo, rodent and human models, the dysregulation occurring in skeletal muscle as a result of the persistent inflammation that may contribute to the structural and functional outcomes reported in rheumatoid cachexia, as well as how this dysregulation may potentially be addressed via modulation by BMP-7.