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postgraduate thesis: Role of endothelin-1 in chondrocyte differentiation and cartilage homeostasis

TitleRole of endothelin-1 in chondrocyte differentiation and cartilage homeostasis
Authors
Issue Date2017
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Zhao, W. [赵伟玮]. (2017). Role of endothelin-1 in chondrocyte differentiation and cartilage homeostasis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractCurrently, osteoarthritis (OA) is recognized as a heterogeneous disease with a variety of causes. The initiation and progression of OA cannot be accounted for by mechanical stress alone. There is an increasing body of evidence showing that systemic conditions, such as chronic inflammation and metabolic disorders, contribute to the development of OA. Given the high frequency of OA’s co-occurrence with cardiovascular diseases (CVDs) and metabolic syndrome (MetS), special attention has been paid to studying the common mechanisms underlying those systemic diseases. Unraveling the common biological pathways would benefit our understanding of the pathogenesis of metabolic OA as well as the development of novel drugs for OA treatment. The view that endothelin-1 (ET-1) plays a critical role in the cardiovascular system arose from a number of observations that levels of plasma ET-1 were found to be significantly upregulated in patients with CVDs and MetS. More recently, it was suggested that ET-1 promoted cartilage degradation via collagenase upregulation. Thereby, we hypothesized that the alteration of systemic ET-1 would affect the vascular functions as well as the cartilage homeostasis. In this study, we aimed to investigate the role of ET-1 in chondrocyte differentiation and cartilage homeostasis. The predominant expression of ET-1 in hypertrophic chondrocytes was detected, suggesting the association of ET-1 signaling with chondrocyte hypertrophy. The overexpression of endothelial ET-1 resulted in slight dwarfism in neonatal mice, which was attributed to the activity of ET-1 in endochondral ossification initiated by the hypertrophic differentiation of chondrocytes. Age-related spontaneous cartilage degeneration was found in transgenic mice overexpressing endothelial ET-1 (TET-1 mice), suggesting that the elevation of systemic ET-1 affected the homeostasis of articular cartilage. An increased number of type Ⅹ collagen positive chondrocytes in un-calcified cartilage was identified. Furthermore, accelerated progression of traumatic OA was observed in TET-1 mice. In vitro study showed that ET-1 facilitated chondrocyte hypertrophy by increasing the expression of hypertrophic markers. These results suggested increased ET-1 promoted cartilage degeneration probably via the regulation of chondrocyte hypertrophy. Taken together, we have demonstrated the role of systemic ET-1 in chondrocyte hypertrophy, endochondral ossification, cartilage maintenance, and OA. This is the first in vivo study to investigate the effect of elevated systemic ET-1 on chondrocytes and cartilage, contributing to the knowledge about ET-1’s role in the skeletal system.
DegreeDoctor of Philosophy
SubjectCartilage cells
Cell differentiation
Endothelins
Dept/ProgramOrthopaedics and Traumatology
Persistent Identifierhttp://hdl.handle.net/10722/244289

 

DC FieldValueLanguage
dc.contributor.authorZhao, Weiwei-
dc.contributor.author赵伟玮-
dc.date.accessioned2017-09-08T08:33:30Z-
dc.date.available2017-09-08T08:33:30Z-
dc.date.issued2017-
dc.identifier.citationZhao, W. [赵伟玮]. (2017). Role of endothelin-1 in chondrocyte differentiation and cartilage homeostasis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/244289-
dc.description.abstractCurrently, osteoarthritis (OA) is recognized as a heterogeneous disease with a variety of causes. The initiation and progression of OA cannot be accounted for by mechanical stress alone. There is an increasing body of evidence showing that systemic conditions, such as chronic inflammation and metabolic disorders, contribute to the development of OA. Given the high frequency of OA’s co-occurrence with cardiovascular diseases (CVDs) and metabolic syndrome (MetS), special attention has been paid to studying the common mechanisms underlying those systemic diseases. Unraveling the common biological pathways would benefit our understanding of the pathogenesis of metabolic OA as well as the development of novel drugs for OA treatment. The view that endothelin-1 (ET-1) plays a critical role in the cardiovascular system arose from a number of observations that levels of plasma ET-1 were found to be significantly upregulated in patients with CVDs and MetS. More recently, it was suggested that ET-1 promoted cartilage degradation via collagenase upregulation. Thereby, we hypothesized that the alteration of systemic ET-1 would affect the vascular functions as well as the cartilage homeostasis. In this study, we aimed to investigate the role of ET-1 in chondrocyte differentiation and cartilage homeostasis. The predominant expression of ET-1 in hypertrophic chondrocytes was detected, suggesting the association of ET-1 signaling with chondrocyte hypertrophy. The overexpression of endothelial ET-1 resulted in slight dwarfism in neonatal mice, which was attributed to the activity of ET-1 in endochondral ossification initiated by the hypertrophic differentiation of chondrocytes. Age-related spontaneous cartilage degeneration was found in transgenic mice overexpressing endothelial ET-1 (TET-1 mice), suggesting that the elevation of systemic ET-1 affected the homeostasis of articular cartilage. An increased number of type Ⅹ collagen positive chondrocytes in un-calcified cartilage was identified. Furthermore, accelerated progression of traumatic OA was observed in TET-1 mice. In vitro study showed that ET-1 facilitated chondrocyte hypertrophy by increasing the expression of hypertrophic markers. These results suggested increased ET-1 promoted cartilage degeneration probably via the regulation of chondrocyte hypertrophy. Taken together, we have demonstrated the role of systemic ET-1 in chondrocyte hypertrophy, endochondral ossification, cartilage maintenance, and OA. This is the first in vivo study to investigate the effect of elevated systemic ET-1 on chondrocytes and cartilage, contributing to the knowledge about ET-1’s role in the skeletal system. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshCartilage cells-
dc.subject.lcshCell differentiation-
dc.subject.lcshEndothelins-
dc.titleRole of endothelin-1 in chondrocyte differentiation and cartilage homeostasis-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineOrthopaedics and Traumatology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2017-
dc.identifier.mmsid991043953697503414-

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