Millar, Neal Lindsay
The role of inflammation and cytokines in the pathogenesis of tendinopathy.
PhD thesis, University of Glasgow.
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Tendon disorders - tendinopathies - are the primary reason form musculoskeletal consultation in primary care in the UK and the US. The molecular pathophysiology of tendinopathy remains difficult to interpret while inflammation and its role in tendinopathy have been historically ignored due to its absence in human surgical specimens. This thesis explores the role of inflammation in human tendinopathy and dissects potential molecular pathways involved in its initiation and perpetuation.
Firstly I characterize inflammatory cell subtypes within a model of human tendinopathy highlighting a distinct inflammatory infiltrate particularly of mast cells
and macrophages. Hypoxia and hypoxic cell death have been a long considered aetiology of tendon degeneration. In this thesis I demonstrate that hypoxia related
proteins are present in early tendinopathy biopsies and thereafter in mechanistic studies demonstrate that hypoxia regulates inflammatory and apoptotic mediators
in tendon cells associated with a significant shift in collagen matrix synthesis.
The cytokines, interleukins 17 and 33 are emerging inflammatory mediators known to play key roles in fibroblast biology. I explored the cellular sources of IL-
17A in human tendinopathy with experiments revealing the majority of IL17A colocalised to mast cells. Moreover IL-17A induced proinflammatory cytokines and apoptosis in vitro and again resulted in a significant switch in collagen extracellular matrix production. IL 33 is a new member of the IL-1 superfamily that signals through the ST2 receptor. Herein I demonstrate that IL-33 expression is up regulated in human tendinopathic biopsies whilst rhIL-33 promotes proinflammatory cytokine release and significantly shifts matrix production toward
a collagen III phenotype. WT mice undergoing a tendon injury model showed significant up regulation of IL-33 and ST2 while ST2-/- mice exhibit a reduced collagen response and biomechanical tendon strength at early time points post
injury Addition of rh-IL33 increased type III collagen production and reduced the biomechanical strength of WT tendons. Furthermore mechanistic investigations has highlighted a key role for the microRNA 29 family in the modulation of collagen regulation in tendinopathy but also in controlling IL-33 induced changes as a direct
target of sST2. Based on these experiments I propose IL-33 as an important and influential alarmin in early tendon injury and tendinopathy, which may be influential
in the balance between reparation and degeneration in tendon disease.
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