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Trapidil promotes osteogenesis by activating the signaling of BMP : 뼈형성단백질 신호전달경로 활성화를 통한 트라피딜의 골형성 촉진
DC Field | Value | Language |
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dc.contributor.advisor | 이장희 | - |
dc.contributor.author | 김봉준 | - |
dc.date.accessioned | 2018-05-28T17:18:13Z | - |
dc.date.available | 2018-05-28T17:18:13Z | - |
dc.date.issued | 2018-02 | - |
dc.identifier.other | 000000149732 | - |
dc.identifier.uri | https://hdl.handle.net/10371/141201 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 치의학대학원 치의과학과, 2018. 2. 이장희. | - |
dc.description.abstract | however, an imbalance between these processes causes osteopathic diseases, such as osteoporosis. For osteoporosis therapy, anti-osteoclastic drugs are used to attenuate the upregulated osteoclast activity. However, anti-osteoclasts agents cannot restore already destroyed bone. Thus, bone anabolic agents are required. Studies have shown that inhibition of platelet-derived growth factor receptor (PDGFR) signaling promotes osteogenesis in vitro. However, the therapeutic efficacy of inhibiting PDGF signaling in bone regeneration in vivo and the specific mechanisms by which PDGFR signaling inhibits osteogenic differentiation remain unclear. In the present study, the osteogenic effect of PDGFR inhibition was examined using a PDGFR antagonist, trapidil, in vivo and in vitro, and its mechanisms were evaluated. A rat calvarial defect model was analyzed using micro-computed tomography and histology to determine the pro-osteogenic effect of trapidil in vivo. Trapidil greatly promoted bone regeneration of a defected rat calvariae. In addition, primary mouse calvarial osteoblast precursors were cultured in osteogenic differentiation medium containing trapidil to study the mechanisms. Trapidil induced phosphorylation of Smad1/5/9 and mitogen-activated protein kinase (MAPK), enhancing the expression of runt-related transcription factor 2 (Runx2), a crucial transcription factor for osteogenesis. The pro-osteogenic effects of trapidil were inhibited by LDN193189, a specific inhibitor of the bone morphogenetic protein receptor (BMPR), activin receptor-like kinase 2 (ALK2) and ALK3, and by treatment with a BMP antagonist noggin, as well as ALK3 depletion. Moreover, trapidil showed a synergistic effect with human recombinant BMP2 on osteogenic differentiation. In conclusion, our results demonstrate that trapidil induces osteogenesis through activation of BMP signalling, and that the attenuated PDGFR signalling is involved in the bio-reactivity of a type ⅠBMP receptor, ALK3. | - |
dc.description.abstract | Bone is a continuously renewing tissue which its mass is finely balanced by the bone-forming and -resorbing cells, osteoblasts and osteoclasts, respectively | - |
dc.description.tableofcontents | INTRODUCTION 1
MATERIALS AND METHODS 14 Animal 14 Rat calvarial defect model 14 μCT and histomorphometric analysis 15 Cell culture and osteogenic differentiation 16 ALP staining and activity 17 Electrophoration and luciferase reporter assay 18 Viral gene transduction 19 Cell viability assay 20 Immunoblotting 21 Reverse transcription and real-time PCR analysis 21 Statistical analysis 22 RESULTS 24 Trapidil promotes bone regeneration in vivo 24 Trapidil enhances osteogenic differentiation in vitro 28 Trapidil induces BMPR signaling 40 Inhibition of PDGF signaling induces BMP signaling 49 ALK3 is required for the trapidil-induced osteogenesis 54 Trapidil induces BMP-mediated BMPR activity 61 Akt is involved in trapidil-induced osteogenesis, however, CREB is not involved in 66 Trapidil inhibits PDGFRα 74 DISCUSSION 78 REFERENCES 85 ABSTRACT IN KOREAN 95 | - |
dc.format | application/pdf | - |
dc.format.extent | 4456981 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Trapidil | - |
dc.subject | Osteoblast | - |
dc.subject | PDGF | - |
dc.subject | BMP | - |
dc.subject | Osteogenesis | - |
dc.subject.ddc | 617.6 | - |
dc.title | Trapidil promotes osteogenesis by activating the signaling of BMP | - |
dc.title.alternative | 뼈형성단백질 신호전달경로 활성화를 통한 트라피딜의 골형성 촉진 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Bongjun Kim | - |
dc.description.degree | Doctor | - |
dc.contributor.affiliation | 치의학대학원 치의과학과 | - |
dc.date.awarded | 2018-02 | - |
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