Krawetz, Roman J.Ren, Guomin2018-10-102018-10-102018-09-20http://hdl.handle.net/1880/108829Osteoarthritis (OA) is one of the most common chronic diseases worldwide which can lead to disability. There is a desperate need for the efficient and reliable detection of OA at the early stage when patients are likely to benefit most from disease interventions. It has been shown in previous studies that inflammation plays important roles in cartilage degeneration, synovitis, remodeling of the subchondral bone and pain. The purpose of this thesis was to determine if a panel of inflammatory cytokines were distinct within individuals with pre-radiographic OA and/or an increased risk of developing OA. Serum inflammatory profiles were analyzed within a number of patient cohorts [i.e., radiographic OA patients (hip and knee), youth with a history of intra-articular knee injury, corresponding controls]; and it was found that inflammatory profiles were distinct between knee vs. hip OA patients. Additionally, a computation method was developed which identified a coordinated change in cytokine profiles in the youth knee injury cohort. This computational methodology highlighted a number of candidate biomarkers that contributed to this observed difference, including C-C motif chemokine 22 (CCL22)/macrophage derived chemokine (MDC) which was selected for further study. In a pre-clinical rat OA model, it was found that CCL22 plays a functional role in chondrocyte apoptosis and cartilage degeneration. Further, it was found that CCL22 treated synovial fibroblasts demonstrated altered expression of inflammatory factors. These results suggested that CCL22 may be a biomarker and potential drug target in early OA. These results also suggested that CCL22 may be associated with OA pain, yet this was not examined directly and an in vivo model where CCL22 expression could be regulated would be required to test this hypothesis. While it was observed that CCL22 is expressed in damaged cartilage and acts on human chondrocytes and synovial fibroblasts, additional studies are required to determine how CCL22 triggered these changes in synovial fibroblasts as these results suggest this is CCR4 independent. Furthermore, it would be essential to validate these findings in an independent cohort to examine the sensitivity and/or specificity of CCL22 as an early OA biomarker.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Engineering--Biomedicaldoctoral thesis10.11575/PRISM/33169