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An Investigation into BMP9-induced postnatal maturation of articular cartilage / MILES ANDERSON-WATTERS

Swansea University Author: MILES ANDERSON-WATTERS

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Abstract

Postnatal maturation is a process of articular cartilage development in which the tissue acquires biomechanical properties allowing lifelong cyclical loading in adults. During postnatal maturation cartilage undergoes structural and morphological changes, including the reorganisation of the collagen...

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Published: Swansea, Wales, UK 2023
Institution: Swansea University
Degree level: Master of Research
Degree name: MSc by Research
Supervisor: Khan, Ilyas M.
URI: https://cronfa.swan.ac.uk/Record/cronfa66306
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During postnatal maturation cartilage undergoes structural and morphological changes, including the reorganisation of the collagen network from isotropic to one that is anisotropic, forming distinct zonal regions of collagen architecture and chondrocyte organisation. However, the mechanisms underlying the process of maturation are poorly understood. Currently there are no in vitro biological models of maturation, limiting study of this phenomenon to snapshots of histological, biochemical and biophysical changes. In this study we have shown that in situ culture of immature bovine cartilage explants with BMP9 induces changes in collagen structure and chondrocyte organisation recapitulating the zonal features of mature articular cartilage. We found BMP9 stimulates reorganisation of the collagen network causing the reorientation of mid and deep zone fibres perpendicular to the cartilage surface. Inhibition of matrix metalloproteinases (MMPs) via doxycycline prevented the changes observed in collagen alignment. Our results demonstrate that there is increased MMP3 expression and a reduction in tissue inhibitors of metalloproteinases-1 and -2 resulting in an increase in proteoglycan turnover and uptake of water. Of significant note were observations that show that cellular proliferation is involved in maturation, contrary to findings in mouse cartilage postnatal development, and immunological data showing that remodelling of collagen does not require enzymatic cleavage of pre-existing fibres. Whilst observations of BMP9 induced postnatal maturation in explants were variable, in vitro analysis using isolated chondrocytes grown as pellet cultures provided unequivocal evidence of the role of BMP9 in postnatal organisation of collagen fibrils in immature chondrocytes. In addition, pellet cultures show that mature chondrocytes have an intrinsic ability to recapitulate the mature cartilage collagen architecture, but even this is enhanced in the presence of BMP9. Therefore, we have developed useful models of postnatal maturation that have shone light on several important mechanisms that regulate the transition to maturity. 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This thesis is released under the terms of a Creative Commons Attribution-Non-Commercial-Share Alike (CC-BY-NC- SA) license. Third party content is excluded for use under the license terms.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by-nc-sa/4.0/deed.en</licence></document></documents><OutputDurs/></rfc1807>
spelling v2 66306 2024-05-06 An Investigation into BMP9-induced postnatal maturation of articular cartilage 84005278531fcc12cd1f7311e16d74e6 MILES ANDERSON-WATTERS MILES ANDERSON-WATTERS true false 2024-05-06 Postnatal maturation is a process of articular cartilage development in which the tissue acquires biomechanical properties allowing lifelong cyclical loading in adults. During postnatal maturation cartilage undergoes structural and morphological changes, including the reorganisation of the collagen network from isotropic to one that is anisotropic, forming distinct zonal regions of collagen architecture and chondrocyte organisation. However, the mechanisms underlying the process of maturation are poorly understood. Currently there are no in vitro biological models of maturation, limiting study of this phenomenon to snapshots of histological, biochemical and biophysical changes. In this study we have shown that in situ culture of immature bovine cartilage explants with BMP9 induces changes in collagen structure and chondrocyte organisation recapitulating the zonal features of mature articular cartilage. We found BMP9 stimulates reorganisation of the collagen network causing the reorientation of mid and deep zone fibres perpendicular to the cartilage surface. Inhibition of matrix metalloproteinases (MMPs) via doxycycline prevented the changes observed in collagen alignment. Our results demonstrate that there is increased MMP3 expression and a reduction in tissue inhibitors of metalloproteinases-1 and -2 resulting in an increase in proteoglycan turnover and uptake of water. Of significant note were observations that show that cellular proliferation is involved in maturation, contrary to findings in mouse cartilage postnatal development, and immunological data showing that remodelling of collagen does not require enzymatic cleavage of pre-existing fibres. Whilst observations of BMP9 induced postnatal maturation in explants were variable, in vitro analysis using isolated chondrocytes grown as pellet cultures provided unequivocal evidence of the role of BMP9 in postnatal organisation of collagen fibrils in immature chondrocytes. In addition, pellet cultures show that mature chondrocytes have an intrinsic ability to recapitulate the mature cartilage collagen architecture, but even this is enhanced in the presence of BMP9. Therefore, we have developed useful models of postnatal maturation that have shone light on several important mechanisms that regulate the transition to maturity. We anticipate that our models of BMP9 induced postnatal maturation will provide the basis for further research into understanding the detailed mechanisms involved, guiding the development of more successful tissue engineering strategies. E-Thesis Swansea, Wales, UK BMP9, Articular Cartilage, Collagen, Postnatal-maturation, Tissue engineering, MMPs 2 8 2023 2023-08-02 COLLEGE NANME COLLEGE CODE Swansea University Khan, Ilyas M. Master of Research MSc by Research 2024-05-06T13:17:59.6658083 2024-05-06T12:41:35.4476489 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science MILES ANDERSON-WATTERS 1 66306__30280__08d359f9829949f1bca4b01376d8eb0c.pdf Anderson-Watters_Miles_C_MSc_Research_Thesis_Final_Redacted_Signature.pdf 2024-05-06T13:02:31.8446212 Output 16239111 application/pdf E-Thesis – open access true Copyright: The Author, Miles Christopher Anderson-Watters, 2023. This thesis is released under the terms of a Creative Commons Attribution-Non-Commercial-Share Alike (CC-BY-NC- SA) license. Third party content is excluded for use under the license terms. true eng https://creativecommons.org/licenses/by-nc-sa/4.0/deed.en
title An Investigation into BMP9-induced postnatal maturation of articular cartilage
spellingShingle An Investigation into BMP9-induced postnatal maturation of articular cartilage
MILES ANDERSON-WATTERS
title_short An Investigation into BMP9-induced postnatal maturation of articular cartilage
title_full An Investigation into BMP9-induced postnatal maturation of articular cartilage
title_fullStr An Investigation into BMP9-induced postnatal maturation of articular cartilage
title_full_unstemmed An Investigation into BMP9-induced postnatal maturation of articular cartilage
title_sort An Investigation into BMP9-induced postnatal maturation of articular cartilage
author_id_str_mv 84005278531fcc12cd1f7311e16d74e6
author_id_fullname_str_mv 84005278531fcc12cd1f7311e16d74e6_***_MILES ANDERSON-WATTERS
author MILES ANDERSON-WATTERS
author2 MILES ANDERSON-WATTERS
format E-Thesis
publishDate 2023
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Postnatal maturation is a process of articular cartilage development in which the tissue acquires biomechanical properties allowing lifelong cyclical loading in adults. During postnatal maturation cartilage undergoes structural and morphological changes, including the reorganisation of the collagen network from isotropic to one that is anisotropic, forming distinct zonal regions of collagen architecture and chondrocyte organisation. However, the mechanisms underlying the process of maturation are poorly understood. Currently there are no in vitro biological models of maturation, limiting study of this phenomenon to snapshots of histological, biochemical and biophysical changes. In this study we have shown that in situ culture of immature bovine cartilage explants with BMP9 induces changes in collagen structure and chondrocyte organisation recapitulating the zonal features of mature articular cartilage. We found BMP9 stimulates reorganisation of the collagen network causing the reorientation of mid and deep zone fibres perpendicular to the cartilage surface. Inhibition of matrix metalloproteinases (MMPs) via doxycycline prevented the changes observed in collagen alignment. Our results demonstrate that there is increased MMP3 expression and a reduction in tissue inhibitors of metalloproteinases-1 and -2 resulting in an increase in proteoglycan turnover and uptake of water. Of significant note were observations that show that cellular proliferation is involved in maturation, contrary to findings in mouse cartilage postnatal development, and immunological data showing that remodelling of collagen does not require enzymatic cleavage of pre-existing fibres. Whilst observations of BMP9 induced postnatal maturation in explants were variable, in vitro analysis using isolated chondrocytes grown as pellet cultures provided unequivocal evidence of the role of BMP9 in postnatal organisation of collagen fibrils in immature chondrocytes. In addition, pellet cultures show that mature chondrocytes have an intrinsic ability to recapitulate the mature cartilage collagen architecture, but even this is enhanced in the presence of BMP9. Therefore, we have developed useful models of postnatal maturation that have shone light on several important mechanisms that regulate the transition to maturity. We anticipate that our models of BMP9 induced postnatal maturation will provide the basis for further research into understanding the detailed mechanisms involved, guiding the development of more successful tissue engineering strategies.
published_date 2023-08-02T13:17:58Z
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