Identification of important interactions between subchondral bone ...

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Contents CHAPTER 4 PAPER I ...................................................................................................................................................... 51 CHAPTER 5 PAPER II .................................................................................................................................................... 67 CHAPTER 6 PAPER III ................................................................................................................................................... 77 CHAPTER 7 PAPER IV ................................................................................................................................................... 89 CHAPTER 8 General discussion and conclusions ...................................................................................................... 101 Future perspectives .................................................................................................................................. 103 Abbreviations ............................................................................................................................................ 104 Appendix I ................................................................................................................................................. 105 Co-author declarations for paper I - IV .......................................................................................... 105 Appendix II ............................................................................................................................................... 112 Publication list ...................................................................................................................................... 112 6
Abstract Abstract Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability, with prevalence increasing with age. At present there are no structure modifying treatments accepted by the Food and Drug Administration (FDA), emphasizing the need for understanding the pathogenic processes leading to OA. OA is a complex disease of the entire joint, including bone, cartilage and the synovium, and it is characterized by the progressive degradation of articular cartilage, mild synovial inflammation, and alterations of the subchondral bone. Currently, it is not clear whether the pathogenesis of OA originates in the bone or cartilage compartment, and little is still known on how these compartments drive disease progression. An increased amount of evidence suggests a strong coupling between the subchondral bone and the articular cartilage turnover, with pathological processes occurring simultaneously in both compartments. Therefore, an optimal intervention strategy for OA likely includes targeting both bone and cartilage compartments. The aim of the thesis was to investigate the pathogenesis of OA with respect to bone and cartilage, and the importance of the interaction between the two tissues. Understanding the interactions between osteoclasts, osteoblast and chondrocytes may be essential for the development of future treatments for OA. Before the launch of this thesis, there were no validated pre-clinical models that allowed investigation of whole tissue pathology of OA in one single system, which combined the metabolism of the implicated cell types. Thus, the present thesis focused on the development and characterization of a novel murine ex vivo femur head model, comprising the three major cell types involved in the deterioration of joint structure; the osteoblasts, osteoclasts, and chondrocytes. We have established the ex vivo femur head model with positive and negative controls, which allow the investigation of the interaction between bone and cartilage. Furthermore, by using the novel ex vivo model and other pre-clinical models, we evaluated the effect of glucocorticoids on bone and cartilage and found that the effect of glucocorticoids highly depend on the activation and differential stage of the cell targeted in the joint. The thesis also studied the degradation processes of cartilage, focusing on the two predominant proteins; aggrecan and collagen type II. We investigated the molecular differences between matrix metalloproteinase- and aggrecanase-mediated aggrecan degradation as a consequence of their distinct time-dependent degradation profiles. We found that the aggrecan molecule may be divided into two different protease-specific pools. Furthermore, we investigated the differences between normal and OA cartilage with respect to endogenous proteases (assessed by biochemical markers) and found that the degradation markers are released in part by different proteolytic pathways. 7
Page 1 and 2: F A C U L T Y O F S C I E N C E U N
Page 3 and 4: Supervisors University of Copenhage
Page 5 and 6: Preface Preface The work presented
Page 7: Contents Contents Abstract ........
Page 11 and 12: Sammendrag på dansk Sammendrag på
Page 13 and 14: CHAPTER 1 Objectives CHAPTER 1: Obj
Page 15 and 16: CHAPTER 2 Introduction CHAPTER 2: I
Page 17 and 18: 2.2 Biology of the joint CHAPTER 2:
Page 19 and 20: CHAPTER 2: Introduction Also osteob
Page 21 and 22: CHAPTER 2: Introduction follows nor
Page 23 and 24: CHAPTER 2: Introduction When the jo
Page 25 and 26: CHAPTER 2: Introduction Cartilage i
Page 27 and 28: 2.3 The pathology of Osteoarthritis
Page 29 and 30: CHAPTER 2: Introduction number of a
Page 31 and 32: CHAPTER 2: Introduction Cysteine pr
Page 33 and 34: CHAPTER 2: Introduction include car
Page 35 and 36: 2.4 The effect of Glucocorticoids C
Page 37 and 38: 2.5 References for CHAPTER 2 1 WebM
Page 39 and 40: 51 Lorenz H. and Richter W. Osteoar
Page 41 and 42: 97 Nakamura H., Tanaka M., Masuko-H
Page 43 and 44: 139 Garnero P., Ayral X., Rousseau
Page 45 and 46: CHAPTER 3 Overview of OA models CHA
Page 47 and 48: CHAPTER 3: Overview of OA models of
Page 49 and 50: 3.3 Ex vivo controls CHAPTER 3: Ove
Page 51 and 52: 19 Brandt K.D. Animal models of ost
Page 53 and 54: CHAPTER 4 CHAPTER 4: PAPER I PAPER
Page 55 and 56: 266 Cartilage 2(3) therapy for oste
Page 57 and 58: 268 Cartilage 2(3) Figure 1. Charac
Page 59 and 60:
270 Cartilage 2(3) Figure 4. The ca
Page 61 and 62:
272 Cartilage 2(3) Figure 5. Cytoki
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274 Cartilage 2(3) Figure 6. The an
Page 65 and 66:
276 Cartilage 2(3) supports the inc
Page 67 and 68:
278 Cartilage 2(3) release and rece
Page 69 and 70:
CHAPTER 5 CHAPTER 5: PAPER II PAPER
Page 71 and 72:
leading to fragility fractures [12]
Page 73 and 74:
after 1 week (Fig. 2F). The additio
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use a range of assays ranging from
Page 77 and 78:
still some controversy regarding th
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CHAPTER 6 CHAPTER 6: PAPER III PAPE
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Biomarkers Downloaded from informah
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Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
CHAPTER 7 CHAPTER 7: PAPER IV PAPER
Page 93 and 94:
Introduction CHAPTER 7: PAPER IV Ca
Page 95 and 96:
Bovine articular cartilage experime
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CHAPTER 7: PAPER IV Detection of ke
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CHAPTER 7: PAPER IV The MMP inhibit
Page 101 and 102:
CHAPTER 7: PAPER IV The pre-stimula
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CHAPTER 8 CHAPTER 8: General discus
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Future perspectives CHAPTER 8: Futu
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Appendix I Co-author declarations f
Page 109 and 110:
Appendix I 107
Page 111 and 112:
Appendix I 109
Page 113 and 114:
Appendix I 111
Page 115:
Biochemical Markers of Joint Tissue
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