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postgraduate thesis: Proteoglycans modulation by small molecules for treatment of intervertebral disc degeneration

TitleProteoglycans modulation by small molecules for treatment of intervertebral disc degeneration
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Sun, Y. [孫毅]. (2014). Proteoglycans modulation by small molecules for treatment of intervertebral disc degeneration. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5204897
AbstractProteoglycan (PG) degradation is characterized as one of the first signs within nucleus pulposus (NP) of intervertebral disc (IVD) in the disc degeneration (IDD). PG plays an important role to maintain the disc homeostasis by providing mechanical strength to resist the compression forces. Aging or degeneration can induce an imbalance of anabolic and catabolic activities of PG production to contribute to the IDD. Many therapies are proposed to restore the PG by either suppression of PG degradation or stimulation to PG synthesis, such as the injection of anabolic factors or selective inhibition of catabolic enzymes. However, it is still largely unknown of the regulation mechanisms of PG production in disc degeneration. Under this circumstance, forward chemical genetics approach was adopted to clarify the molecular mechanisms of small molecules to regulate PG production in disc degeneration. Large quantities of synthetic compounds were previously tested for their ability to stimulate PG production. Seven potent compounds were identified as promoters of glycosaminoglycan (GAG) production in chondrocytes and bovine NP cells. This thesis hypothesized that small molecules could modulate PG production pathways, and alleviate disc degeneration. This study aimed to test the seven compounds in modulation of PG production in degenerated human NP cells, and investigate their in vivo effects in a needle stab-induced disc degeneration model. GAG production gave a dose-dependent response to the stimulation from four compounds, namely C3, 4, 5 and 7, in bovine and human degenerated NP cells, suggesting they have favorable specificity in PG regulation. Moreover, the dosedependent increase of PG production was validated by exploring the aggrecan PG expression and GAG deposition in the matrix. Besides, the specific expression pattern of chondroitin sulfate PG, the predominant PG in NP, is further characterized. By using an established injury-induced disc degeneration model, in which the rat caudal discs were punctured by needle penetration through annulus fibrosus into nucleus pulposus, we identified the three potent compounds (C3, 4 and 5) that can prevent the PG decrease in the degeneration. Moreover, two of them (C4 and 5) presented a recovery of disc height in the degenerated discs, suggesting their capacity in alleviating IDD in vivo. Of them, C4 could up-regulate aggrecan gene expression; C5 seemed capable to specifically inhibit interleukin-1 (IL-1)-induced MMP production. The specific inhibition of proteolytic activity was observed for C3, which might be related to expression of active MMP9. Interestingly, C7 showed a remarkable suppression to IL-1 downstream events, but it did not confer to the restoration of PG content in degenerated disc. All these data support that the compounds identified have specific modulatory action on proteoglycans production via interfering either anabolic or catabolic pathways, and can function to delay or reverse the disc degeneration.
DegreeDoctor of Philosophy
SubjectIntervertebral disk - Diseases
Proteoglycans
Dept/ProgramOrthopaedics and Traumatology
Persistent Identifierhttp://hdl.handle.net/10722/225836

 

DC FieldValueLanguage
dc.contributor.authorSun, Yi-
dc.contributor.author孫毅-
dc.date.accessioned2016-05-20T23:15:37Z-
dc.date.available2016-05-20T23:15:37Z-
dc.date.issued2014-
dc.identifier.citationSun, Y. [孫毅]. (2014). Proteoglycans modulation by small molecules for treatment of intervertebral disc degeneration. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5204897-
dc.identifier.urihttp://hdl.handle.net/10722/225836-
dc.description.abstractProteoglycan (PG) degradation is characterized as one of the first signs within nucleus pulposus (NP) of intervertebral disc (IVD) in the disc degeneration (IDD). PG plays an important role to maintain the disc homeostasis by providing mechanical strength to resist the compression forces. Aging or degeneration can induce an imbalance of anabolic and catabolic activities of PG production to contribute to the IDD. Many therapies are proposed to restore the PG by either suppression of PG degradation or stimulation to PG synthesis, such as the injection of anabolic factors or selective inhibition of catabolic enzymes. However, it is still largely unknown of the regulation mechanisms of PG production in disc degeneration. Under this circumstance, forward chemical genetics approach was adopted to clarify the molecular mechanisms of small molecules to regulate PG production in disc degeneration. Large quantities of synthetic compounds were previously tested for their ability to stimulate PG production. Seven potent compounds were identified as promoters of glycosaminoglycan (GAG) production in chondrocytes and bovine NP cells. This thesis hypothesized that small molecules could modulate PG production pathways, and alleviate disc degeneration. This study aimed to test the seven compounds in modulation of PG production in degenerated human NP cells, and investigate their in vivo effects in a needle stab-induced disc degeneration model. GAG production gave a dose-dependent response to the stimulation from four compounds, namely C3, 4, 5 and 7, in bovine and human degenerated NP cells, suggesting they have favorable specificity in PG regulation. Moreover, the dosedependent increase of PG production was validated by exploring the aggrecan PG expression and GAG deposition in the matrix. Besides, the specific expression pattern of chondroitin sulfate PG, the predominant PG in NP, is further characterized. By using an established injury-induced disc degeneration model, in which the rat caudal discs were punctured by needle penetration through annulus fibrosus into nucleus pulposus, we identified the three potent compounds (C3, 4 and 5) that can prevent the PG decrease in the degeneration. Moreover, two of them (C4 and 5) presented a recovery of disc height in the degenerated discs, suggesting their capacity in alleviating IDD in vivo. Of them, C4 could up-regulate aggrecan gene expression; C5 seemed capable to specifically inhibit interleukin-1 (IL-1)-induced MMP production. The specific inhibition of proteolytic activity was observed for C3, which might be related to expression of active MMP9. Interestingly, C7 showed a remarkable suppression to IL-1 downstream events, but it did not confer to the restoration of PG content in degenerated disc. All these data support that the compounds identified have specific modulatory action on proteoglycans production via interfering either anabolic or catabolic pathways, and can function to delay or reverse the disc degeneration.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshIntervertebral disk - Diseases-
dc.subject.lcshProteoglycans-
dc.titleProteoglycans modulation by small molecules for treatment of intervertebral disc degeneration-
dc.typePG_Thesis-
dc.identifier.hkulb5204897-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineOrthopaedics and Traumatology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5204897-

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