Inflammation in osteoarthritis – a focus on the role of interleukin-17
<p>Osteoarthritis (OA) is increasingly accepted as a whole joint disease, with an important role for synovial inflammation (synovitis) in its pathophysiology. However, there is limited knowledge about underlying OA biology, including the influx of immune cells, the activation status of fibrobl...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2019
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| _version_ | 1817931630532100096 |
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| author | Mimpen, J |
| author2 | Snelling, S |
| author_facet | Snelling, S Mimpen, J |
| author_sort | Mimpen, J |
| collection | OXFORD |
| description | <p>Osteoarthritis (OA) is increasingly accepted as a whole joint disease, with an important role for synovial inflammation (synovitis) in its pathophysiology. However, there is limited knowledge about underlying OA biology, including the influx of immune cells, the activation status of fibroblasts, and the critical cytokine mediators of disease. One family of cytokines that has received increasing interest is interleukin (IL)-17. IL-17A and its family members IL-17F and IL-17AF are known to play an important role in inflammatory (musculoskeletal) diseases such as psoriasis and ankylosing spondylitis. Initial studies have suggested a role for IL-17A in OA, but there is still limited knowledge on the expression of IL-17 cytokines and receptors in OA tissue, the effect of IL-17 on cells from the OA joint, and how this relates to the synovitis seen in OA patients. Therefore, this thesis aimed to advance the understanding of inflammation, and specifically the role of IL-17 cytokines, in OA pathophysiology. </p>
<p>This thesis uses flow cytometry to show that there is significant infiltration of immune cells, especially T cells and macrophages, in the synovium from patients with end-stage OA. Fibroblasts in end-stage OA synovium show an activated phenotype, with a predominant immune effector population, which might be an important contributor to the synovitis seen in many patients. In patients that have a high risk of developing post-traumatic OA, immunohistochemistry showed that macrophage markers positively correlated with a histological synovitis score, which supports the hypothesis that macrophages are a key driver of synovitis. These findings do not only highlight the importance of inflammation in OA, but also stress the importance of synovium in OA, thereby providing further evidence for OA as a disease of the whole joint.</p>
<p>This thesis also supports that IL-17 cytokines can play an important role in OA. A potential Th17 subset (CCR6+ T cells) was found in a subset of end-stage patients. In synovium from patients at high risk of developing post-traumatic OA, IL-17A and its receptors IL-17RA and IL-17RC were expressed. In addition, expression of IL-17RA positively correlated with a histological synovitis score, potentially making this tissue more susceptible to respond to IL-17 cytokines. Gene expression of IL17RA and IL17RC in chondrocytes and synovial fibroblasts derived from end-stage OA patients confirms the ability of these cells to respond to IL-17 cytokines. In vitro treatment of these cells from end-stage OA patients with IL-17A, and its family members IL-17F and IL-17AF, induced changes in gene expression in several OA-related pathways including matrix destruction, angiogenesis and inflammation. The chronic, low-grade inflammation seen in OA fits well with these effects of IL-17A and further supports a role for IL-17A in OA pathophysiology. As there are currently no disease-modifying OA drugs, anti-IL-17 therapy could be investigated as a potential therapeutic option in OA patients.</p>
<p>In conclusion, this thesis highlights the importance of inflammation in OA, proposing that IL-17A could be an important mediator in sustaining joint inflammation. In addition, it further demonstrates a role for the synovium in OA, which emphasizes that OA should be viewed as a disease of the whole joint. Future studies should apply modern omics techniques to a larger, well-phenotyped cohort of OA patients to identify subtypes of disease in synovium and other OA joint tissues by unravelling the cellular, molecular, and genetic signatures of disease in a longitudinal study.</p> |
| first_indexed | 2024-03-07T08:28:33Z |
| format | Thesis |
| id | oxford-uuid:006cc101-b9f1-48ac-934b-aa8231abc2e4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:25:05Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:006cc101-b9f1-48ac-934b-aa8231abc2e42024-12-01T08:38:49ZInflammation in osteoarthritis – a focus on the role of interleukin-17Thesishttp://purl.org/coar/resource_type/c_db06uuid:006cc101-b9f1-48ac-934b-aa8231abc2e4OsteoarthritisEnglishORA Deposit2019Mimpen, JSnelling, SDakin, SCarr, A<p>Osteoarthritis (OA) is increasingly accepted as a whole joint disease, with an important role for synovial inflammation (synovitis) in its pathophysiology. However, there is limited knowledge about underlying OA biology, including the influx of immune cells, the activation status of fibroblasts, and the critical cytokine mediators of disease. One family of cytokines that has received increasing interest is interleukin (IL)-17. IL-17A and its family members IL-17F and IL-17AF are known to play an important role in inflammatory (musculoskeletal) diseases such as psoriasis and ankylosing spondylitis. Initial studies have suggested a role for IL-17A in OA, but there is still limited knowledge on the expression of IL-17 cytokines and receptors in OA tissue, the effect of IL-17 on cells from the OA joint, and how this relates to the synovitis seen in OA patients. Therefore, this thesis aimed to advance the understanding of inflammation, and specifically the role of IL-17 cytokines, in OA pathophysiology. </p> <p>This thesis uses flow cytometry to show that there is significant infiltration of immune cells, especially T cells and macrophages, in the synovium from patients with end-stage OA. Fibroblasts in end-stage OA synovium show an activated phenotype, with a predominant immune effector population, which might be an important contributor to the synovitis seen in many patients. In patients that have a high risk of developing post-traumatic OA, immunohistochemistry showed that macrophage markers positively correlated with a histological synovitis score, which supports the hypothesis that macrophages are a key driver of synovitis. These findings do not only highlight the importance of inflammation in OA, but also stress the importance of synovium in OA, thereby providing further evidence for OA as a disease of the whole joint.</p> <p>This thesis also supports that IL-17 cytokines can play an important role in OA. A potential Th17 subset (CCR6+ T cells) was found in a subset of end-stage patients. In synovium from patients at high risk of developing post-traumatic OA, IL-17A and its receptors IL-17RA and IL-17RC were expressed. In addition, expression of IL-17RA positively correlated with a histological synovitis score, potentially making this tissue more susceptible to respond to IL-17 cytokines. Gene expression of IL17RA and IL17RC in chondrocytes and synovial fibroblasts derived from end-stage OA patients confirms the ability of these cells to respond to IL-17 cytokines. In vitro treatment of these cells from end-stage OA patients with IL-17A, and its family members IL-17F and IL-17AF, induced changes in gene expression in several OA-related pathways including matrix destruction, angiogenesis and inflammation. The chronic, low-grade inflammation seen in OA fits well with these effects of IL-17A and further supports a role for IL-17A in OA pathophysiology. As there are currently no disease-modifying OA drugs, anti-IL-17 therapy could be investigated as a potential therapeutic option in OA patients.</p> <p>In conclusion, this thesis highlights the importance of inflammation in OA, proposing that IL-17A could be an important mediator in sustaining joint inflammation. In addition, it further demonstrates a role for the synovium in OA, which emphasizes that OA should be viewed as a disease of the whole joint. Future studies should apply modern omics techniques to a larger, well-phenotyped cohort of OA patients to identify subtypes of disease in synovium and other OA joint tissues by unravelling the cellular, molecular, and genetic signatures of disease in a longitudinal study.</p> |
| spellingShingle | Osteoarthritis Mimpen, J Inflammation in osteoarthritis – a focus on the role of interleukin-17 |
| title | Inflammation in osteoarthritis – a focus on the role of interleukin-17 |
| title_full | Inflammation in osteoarthritis – a focus on the role of interleukin-17 |
| title_fullStr | Inflammation in osteoarthritis – a focus on the role of interleukin-17 |
| title_full_unstemmed | Inflammation in osteoarthritis – a focus on the role of interleukin-17 |
| title_short | Inflammation in osteoarthritis – a focus on the role of interleukin-17 |
| title_sort | inflammation in osteoarthritis a focus on the role of interleukin 17 |
| topic | Osteoarthritis |
| work_keys_str_mv | AT mimpenj inflammationinosteoarthritisafocusontheroleofinterleukin17 |