부산대학교 도서관

Although pathogenesis of musculoskeletal diseases is incompletely understood, the role of inflammation is now accepted to be important. The microbiome - all non-human microbiota residing in humans - is increasingly of interest as a potential trigger of musculoskeletal disease. Using surrogates for an altered microbiome state (dysbiosis), this thesis employed three scientific approaches to determine whether the microbiome has a role in tendinopathy. Firstly, epidemiological (case-control, cross-sectional studies) approaches identified and verified an association between inflammatory bowel disease (IBD) and tendinopathy (OR 2.11, 95% CI 2.08-2.15) and rate of IBD in tendinopathy patients (standardised rate of 19.7%); and confirmed the association between IBD and RA (OR 1.88, 1.70-2.07). Secondly, pharmaco-epidemiological (case-control) techniques found an association between beta-lactam and tetracycline antibiotics, (OR 1.59, 1.57-1.60 and OR 1.08, 1.06-1.11 respectively) and tendinopathy. Similar trends were found between beta-lactam and quinolone usage and tendon ruptures (OR 1.42, 1.27-1.58 and OR 1.11, 0.97-1.27 respectively). Index RA was associated with beta-lactam and quinolone use (OR 1.32, 1.26-1.38 and OR 1.23, 1.16-1.29 respectively). These associations were dose-dependent and demonstrated a temporal association. Moreover, a self-controlled case series study found an association between RA flares and sulphonamide and trimethoprim use between one and twelve months after prescription. Thirdly, an experimental murine model of tendinopathy was validated (at 72-hours, two-weeks and ten-weeks post-injury). This showed reproducible tendinopathy-relevant changes in histological scores (including calcification) and gene expression (RNAseq). This model was propagated using mice raised in germ-free (GF) or specific pathogen free (SPF) conditions at ten-weeks post injury. There was no significant difference in histological scores, however, significantly lower ossification was observed in mice raised in GF conditions (0.0058mm3 ±0.0017 in GF vs 0.0488mm3 ±0.0197 in SPF, p<0.0001). This thesis demonstrates an association between dysbiosis (IBD, antibiotic usage, SPF over GF conditions) and tendinopathy, suggesting a role for the microbiome in tendinopathy. Further work should investigate the mechanism by which the microbiome mediates tendinopathy.