아주대학교

목차

I. Introduction 1
1. Osteoarthritis 1
2. Cartilage and chondrocytes in OA 2
3. Treatment of OA 3
4. Natural product extracts and single compounds in OA 5
5. BRD4 inhibitors and OA 7
6. Aim of this study 8
II. Material and Methods 11
1. Primary articular mouse chondrocyte culture 11
2. Reagents and Treatments 11
3. Cell viability analysis 12
4. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative reverse transcription PCR (qRT-PCR) 13
5. Western blot analysis 14
6. Prostaglandin E2 (PGE2), collagenase assay and luciferase reporter gene assay 15
7. Animal study in OA mice 16
8. Cartilage tissue histology and immunohistochemistry 17
9. Culture of cartilage explants and Alcian blue staining 17
10. High‐performance liquid chromatography (HPLC) analysis 18
11. Protein structural homology modeling 18
12. RNA-sequencing (RNA-seq) analysis and Ingenuity Pathway Analysis (IPA) 19
13. Statistical analysis 20
III. Results 21
PART I. Inhibitory effect of natural product extracts and single compounds on OA 21
1. Schisandra extract and Schisandrol A suppress OA progression 21
1.1. Schisandra extract regulates catabolic factors induced by IL-1β in mouse articular chondrocytes 21
1.2. Oral gavage of Schisandra extract prevents cartilage destruction in the DMM mouse OA model 26
1.3. Schisandrol A controls catabolic factors in chondrocytes stimulated with IL-1β 30
1.4. Schisandrol A modulates catabolic factors and attenuates cartilage degradation in an experimental OA mouse model 34
1.5. Schisandra extract regulates NF-κB and MAPK signaling pathways 37
2. Safflower seed extract represses OA pathogenesis 43
2.1. Safflower seed extract reduces Mmp3 and Mmp13 levels, and collagenase activity in chondrocytes stimulated by IL-1β 43
2.2. Safflower seed extract attenuates cartilage degradation in a DMM mouse model 47
2.3. N-feruloyl serotonin and N-(p-coumaroyl) serotonin reduce catabolic factors in IL-1β-stimulated chondrocytes 51
2.4. Safflower seed extract, N-feruloyl serotonin and N-(p-coumaroyl) serotonin suppress IL-1β-induced NF-κB signaling 55
PART Ⅱ. Roles of a BRD4 inhibitor, ABC in OA 59
ABC modulates OA progression by controlling catabolic factors 59
1. ABC reduces the expression of IL-1β-induced catabolic factors in mouse articular chondrocytes 59
2. ABC modulates the decay of cartilage in the DMM mouse model 63
3. ABC modulates the IL-1β-induced NF-κB and MAPK signaling pathways in articular chondrocytes 67
IV. Discussion 69
V. Conclusions 82
VI. References 83
국문 초록 104