AbstractThe Toll-like receptors (TLRs) are a family of highly conserved pattern recognition receptors involved in the detection of pathogenic invasion and tissue damage. Activation of TLRs can occur through binding to pathogen associated molecular patterns (PAMPs) but also host derived damage associated molecular patterns (DAMPs), which are highly abundant in the OA joint (Sokolove and Lepus, 2013). Originally thought of as a disease of wear and tear, osteoarthritis (OA) is better described as a disease of chronic inflammation, with the production of pro-inflammatory and degenerative products perpetuating disease activity. Resident joint cells can react through TLRs to these damage products and thereby induce the production and secretion of pro-inflammatory cytokines and matrix degradative enzymes. This study sought to identify TLR expression and activity within synovial fibroblasts categorised by joint location and cartilage sub-categorised by OA progression. TLR induced pro-inflammatory cytokine induction from these cells along with matrix degenerative enzyme production was analysed to determine the pathogenic contribution of the cell types. Significant differences in expression of TLR2, TLR3 and TLR4 were noted between hip and knee derived synovial fibroblasts. Increased expression correlated to a higher pro-inflammatory cytokine production from knee opposed to hip derived synovial fibroblasts. This difference in inflammatory cytokines production comparing knee to hip became even more apparent when observing spontaneous production from synovial membrane cultures that demonstrated TNF, IL-6 and IL-8 to be significantly higher in cultures from the knee opposed to hip. Knee synovial fluid was also noted to have a significantly lower level of MMP1 compared with hip derived samples supporting a hypothesis that knee and hip osteoarthritis pathogeneses may differ. Analysis of articular chondrocytes at different stages of disease progression demonstrated altered phenotypes. Chondrocytes isolated from regions of degeneration had an altered TLR expression pattern and subsequently produced significantly elevated IL-6 and MMP13 following TLR stimulation relative to those isolated from intact regions of cartilage. These data suggest that TLR-induced cytokine secretion by synovial fibroblasts and chondrocytes potentially contribute to disease pathology and hypothetically have two separate phenotypes of disease progression. It also highlights the possible need for tailored treatment of OA dependent on joint location providing some explanation of differences in efficacy of trialled biologic therapies.
|Date of Award||2016|
Study of toll-like receptor expression and activity in hip and knee osteoarthritis
Stephens, M. J. C. (Author). 2016
Student thesis: Doctoral Thesis