Re-evaluating tendon disease: an emerging role for inflammation and alarmins
<p>The importance of inflammation in the pathogenesis of tendon disease (TD) is a subject of ongoing debate. During the past two decades, TD has been principally characterized as a degenerative process devoid of inflammation. This pathological paradigm may disregard a complex role for inflamma...
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| Format: | Thesis |
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2016
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| _version_ | 1826316287634046976 |
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| author | Mosca, M |
| author_facet | Mosca, M |
| author_sort | Mosca, M |
| collection | OXFORD |
| description | <p>The importance of inflammation in the pathogenesis of tendon disease (TD) is a subject of ongoing debate. During the past two decades, TD has been principally characterized as a degenerative process devoid of inflammation. This pathological paradigm may disregard a complex role for inflammation in TD, barring inflammatory cells, mediators, and pathways on the basis that an 'inflammatory infiltrate' is absent in diseased tendons. Improved understanding of inflammation’s cellular and molecular roles in other musculoskeletal diseases prompted a re-emergence of interest in the potential contribution of inflammation to TD. Recent investigations regarding the role of inflammation in TD fuelled the theory that alarmins, endogenous molecules released upon tissue damage, may be instrumental in the pathogenesis of TD.</p> <p>The specific aims of this research were to 1) examine potential explanations for scientific equipoise regarding inflammation's role in TD through a systematic review of the literature and 2) investigate the role of alarmins in the initiation and propagation of TD. We hypothesized that support for an inflammatory component to TD has increased during the last decade, likely due to more thorough interrogations of immune cells and mediators in TD. Additionally, we hypothesized that TD is an alarmin-mediated pathology, with resident tendon cells and macrophages being vital to disease processes.</p> <p>A systematic literature search and quantitative analysis of published reviews whose primary purpose was to examine the pathogenesis of TD was conducted. Reviews’ methodological quality, definitions of the 'inflammatory component', and several other article characteristics were evaluated regarding reviews’ conclusions about the role of inflammation in TD. Logistic regression was performed to determine significant correlates of the conclusion that inflammation plays a role in the pathogenesis of TD. Results revealed growing support for an inflammatory component to TD, particularly during the past 3-6 years. The adoption of a causal theory was significantly associated with greater methodological quality, inclusion of monocytes, macrophages, or lymphocytes, and/or inclusion of signalling molecules, effectors, or growth factors as part of the 'inflammatory component' to TD.</p> <p>Immunopositive staining was determined for a set of alarmins (S100A9, HMGB1, and IL-33) and HIF-1α, an oxygen sensitive transcription factor, in three groups of human supraspinatus tissue: healthy, persistently painful diseased, and treated pain-free tendon samples. Results showed HIF-1α and S100A9 proteins were increased in diseased tissue compared to healthy and post-treatment pain-free tissue; IL-33 was decreased in diseased tissue compared to healthy and post-treatment pain-free tissue. HMGB1 was up regulated in post-treatment pain-free tendon tissue compared to healthy and diseased tissue.</p> <p>This body of work supports a role of inflammation in TD and suggests an alarmin-mediated mechanism. Pathological activation of resident tendon cells and macrophages through alarmin involvement may be clinically significant, resulting in sustained inflammation leading to fibrosis. These findings provide insight into molecular pathways that may lead to novel targets and expand therapeutic options for patients with TD.</p> |
| first_indexed | 2024-03-06T20:46:22Z |
| format | Thesis |
| id | oxford-uuid:360eb093-9a3b-4271-a5b6-31314c7e1bbd |
| institution | University of Oxford |
| last_indexed | 2024-12-09T03:42:12Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | oxford-uuid:360eb093-9a3b-4271-a5b6-31314c7e1bbd2024-12-07T13:21:39ZRe-evaluating tendon disease: an emerging role for inflammation and alarminsThesishttp://purl.org/coar/resource_type/c_bdccuuid:360eb093-9a3b-4271-a5b6-31314c7e1bbdorthopaedicinflammationIL33HIF1aS100a8tendinosisTendinopathyalarminORA Deposit2016Mosca, M<p>The importance of inflammation in the pathogenesis of tendon disease (TD) is a subject of ongoing debate. During the past two decades, TD has been principally characterized as a degenerative process devoid of inflammation. This pathological paradigm may disregard a complex role for inflammation in TD, barring inflammatory cells, mediators, and pathways on the basis that an 'inflammatory infiltrate' is absent in diseased tendons. Improved understanding of inflammation’s cellular and molecular roles in other musculoskeletal diseases prompted a re-emergence of interest in the potential contribution of inflammation to TD. Recent investigations regarding the role of inflammation in TD fuelled the theory that alarmins, endogenous molecules released upon tissue damage, may be instrumental in the pathogenesis of TD.</p> <p>The specific aims of this research were to 1) examine potential explanations for scientific equipoise regarding inflammation's role in TD through a systematic review of the literature and 2) investigate the role of alarmins in the initiation and propagation of TD. We hypothesized that support for an inflammatory component to TD has increased during the last decade, likely due to more thorough interrogations of immune cells and mediators in TD. Additionally, we hypothesized that TD is an alarmin-mediated pathology, with resident tendon cells and macrophages being vital to disease processes.</p> <p>A systematic literature search and quantitative analysis of published reviews whose primary purpose was to examine the pathogenesis of TD was conducted. Reviews’ methodological quality, definitions of the 'inflammatory component', and several other article characteristics were evaluated regarding reviews’ conclusions about the role of inflammation in TD. Logistic regression was performed to determine significant correlates of the conclusion that inflammation plays a role in the pathogenesis of TD. Results revealed growing support for an inflammatory component to TD, particularly during the past 3-6 years. The adoption of a causal theory was significantly associated with greater methodological quality, inclusion of monocytes, macrophages, or lymphocytes, and/or inclusion of signalling molecules, effectors, or growth factors as part of the 'inflammatory component' to TD.</p> <p>Immunopositive staining was determined for a set of alarmins (S100A9, HMGB1, and IL-33) and HIF-1α, an oxygen sensitive transcription factor, in three groups of human supraspinatus tissue: healthy, persistently painful diseased, and treated pain-free tendon samples. Results showed HIF-1α and S100A9 proteins were increased in diseased tissue compared to healthy and post-treatment pain-free tissue; IL-33 was decreased in diseased tissue compared to healthy and post-treatment pain-free tissue. HMGB1 was up regulated in post-treatment pain-free tendon tissue compared to healthy and diseased tissue.</p> <p>This body of work supports a role of inflammation in TD and suggests an alarmin-mediated mechanism. Pathological activation of resident tendon cells and macrophages through alarmin involvement may be clinically significant, resulting in sustained inflammation leading to fibrosis. These findings provide insight into molecular pathways that may lead to novel targets and expand therapeutic options for patients with TD.</p> |
| spellingShingle | orthopaedic inflammation IL33 HIF1a S100a8 tendinosis Tendinopathy alarmin Mosca, M Re-evaluating tendon disease: an emerging role for inflammation and alarmins |
| title | Re-evaluating tendon disease: an emerging role for inflammation and alarmins |
| title_full | Re-evaluating tendon disease: an emerging role for inflammation and alarmins |
| title_fullStr | Re-evaluating tendon disease: an emerging role for inflammation and alarmins |
| title_full_unstemmed | Re-evaluating tendon disease: an emerging role for inflammation and alarmins |
| title_short | Re-evaluating tendon disease: an emerging role for inflammation and alarmins |
| title_sort | re evaluating tendon disease an emerging role for inflammation and alarmins |
| topic | orthopaedic inflammation IL33 HIF1a S100a8 tendinosis Tendinopathy alarmin |
| work_keys_str_mv | AT moscam reevaluatingtendondiseaseanemergingroleforinflammationandalarmins |