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postgraduate thesis: In vivo study of asporin function in cartilage tissues

TitleIn vivo study of asporin function in cartilage tissues
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Lee, K. [李鍵成]. (2014). In vivo study of asporin function in cartilage tissues. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5185915
AbstractAsporin (ASPN) is a risk factor for osteoarthritis and intervertebral disc degeneration. Its expression increases with aging and degeneration. D14 (14 aspartate-repeat polymorphism) is the risk allele and D13 is the most common allele. In vitro studies suggest that Asporin functions as a negative regulator of Tgf-β signaling, an important stimulator of matrix formation in bone and cartilage. However, the in vivo role of Asporin in development or its involvement in the pathogenesis of degenerative cartilage diseases is unclear. Here, we use mouse as a model to study the impact of Asporin in the intervertebral discs of the spine. In wide type mice, we showed that Asporin is expressed and localized in the nucleus pulposus and annulus fibrosis of intervertebral discs, and the articular cartilage in knee joints. Furthermore, Asporin expressing cells in these tissues are active in Tgf-β signaling, suggesting a relationship between Asporin and Tgf-β signaling and a role in disc and articular joint maintenance. Using natural degeneration with aging, and models for induced degeneration in the mouse-tail discs, Asporin expression was shown to be up-regulated in nucleus pulposus and annulus fibrosis cells of degenerating intervertebral discs. These cells are also active in Tgf-β signaling supporting a potential relationship with the pathogenesis of disc degeneration. Transgenic mice overexpressing Asporin in cartilage tissues were generated to study this relationship and the impact on the differentiation and function of disc cells. Interestingly, overexpression of Asporin in the nucleus pulposus leads to enhanced production and deposition of extracellular matrix such as glycosaminoglycans, with concomitant changes in cell morphology, suggesting Asporin altered the extracellular matrix niche of resident nucleus pulposus cells. However, such changes are only observed in discs in the tail region but not in lumbar discs. We propose a relationship to mechanical loading as an environmental factor. Molecular analysis of transgene expressing cells showed Tgf-β signaling is active and its downstream target genes up-regulated. Furthermore, overexpression of Asporin enhances differentiation of notochordal-like cells (NCCs) in mouse nucleus pulposus toward the more mature nucleus pulposus cells (NPCs) and chondrocyte-like cells (CLCs) that are more abundant in the human nucleus pulposus and other larger animals that prompt to intervertebral disc degeneration. This study provided new insights into the function of Asporin in the pathogenesis of intervertebral disc degeneration. We proposed a model whereby Asporin, as a genetic risk factor, alters the extracellular environment of the nucleus pulposus, that in conjunction with environmental factors such as mechanical loading, enhances Tgf-β signaling, and consequentially, promotes the maturation of NCCs towards NPCs and CLCs, a hallmark of degenerative process proposed in human and other larger animal models. These transgenic mice provide the opportunity to better understand the relationship between genetic and environmental factors, and the molecular controls leading to the maturation process of NCCs in intervertebral disc degeneration.
DegreeDoctor of Philosophy
SubjectCartilage - Diseases - Genetic aspects
Dept/ProgramBiochemistry
Persistent Identifierhttp://hdl.handle.net/10722/207898

 

DC FieldValueLanguage
dc.contributor.authorLee, Kin-shing-
dc.contributor.author李鍵成-
dc.date.accessioned2015-01-23T23:18:39Z-
dc.date.available2015-01-23T23:18:39Z-
dc.date.issued2014-
dc.identifier.citationLee, K. [李鍵成]. (2014). In vivo study of asporin function in cartilage tissues. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5185915-
dc.identifier.urihttp://hdl.handle.net/10722/207898-
dc.description.abstractAsporin (ASPN) is a risk factor for osteoarthritis and intervertebral disc degeneration. Its expression increases with aging and degeneration. D14 (14 aspartate-repeat polymorphism) is the risk allele and D13 is the most common allele. In vitro studies suggest that Asporin functions as a negative regulator of Tgf-β signaling, an important stimulator of matrix formation in bone and cartilage. However, the in vivo role of Asporin in development or its involvement in the pathogenesis of degenerative cartilage diseases is unclear. Here, we use mouse as a model to study the impact of Asporin in the intervertebral discs of the spine. In wide type mice, we showed that Asporin is expressed and localized in the nucleus pulposus and annulus fibrosis of intervertebral discs, and the articular cartilage in knee joints. Furthermore, Asporin expressing cells in these tissues are active in Tgf-β signaling, suggesting a relationship between Asporin and Tgf-β signaling and a role in disc and articular joint maintenance. Using natural degeneration with aging, and models for induced degeneration in the mouse-tail discs, Asporin expression was shown to be up-regulated in nucleus pulposus and annulus fibrosis cells of degenerating intervertebral discs. These cells are also active in Tgf-β signaling supporting a potential relationship with the pathogenesis of disc degeneration. Transgenic mice overexpressing Asporin in cartilage tissues were generated to study this relationship and the impact on the differentiation and function of disc cells. Interestingly, overexpression of Asporin in the nucleus pulposus leads to enhanced production and deposition of extracellular matrix such as glycosaminoglycans, with concomitant changes in cell morphology, suggesting Asporin altered the extracellular matrix niche of resident nucleus pulposus cells. However, such changes are only observed in discs in the tail region but not in lumbar discs. We propose a relationship to mechanical loading as an environmental factor. Molecular analysis of transgene expressing cells showed Tgf-β signaling is active and its downstream target genes up-regulated. Furthermore, overexpression of Asporin enhances differentiation of notochordal-like cells (NCCs) in mouse nucleus pulposus toward the more mature nucleus pulposus cells (NPCs) and chondrocyte-like cells (CLCs) that are more abundant in the human nucleus pulposus and other larger animals that prompt to intervertebral disc degeneration. This study provided new insights into the function of Asporin in the pathogenesis of intervertebral disc degeneration. We proposed a model whereby Asporin, as a genetic risk factor, alters the extracellular environment of the nucleus pulposus, that in conjunction with environmental factors such as mechanical loading, enhances Tgf-β signaling, and consequentially, promotes the maturation of NCCs towards NPCs and CLCs, a hallmark of degenerative process proposed in human and other larger animal models. These transgenic mice provide the opportunity to better understand the relationship between genetic and environmental factors, and the molecular controls leading to the maturation process of NCCs in intervertebral disc degeneration.-
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.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshCartilage - Diseases - Genetic aspects-
dc.titleIn vivo study of asporin function in cartilage tissues-
dc.typePG_Thesis-
dc.identifier.hkulb5185915-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineBiochemistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5185915-

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