Identification of important interactions between subchondral bone ...

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Sammendrag på dansk Samlet set har vi etableret en præklinisk fler-vævs model, der kan undersøge celle-celle interaktioner, og som afspejler dele af processerne, man ser i patogenesen af degenerative led- sygdomme. Denne model er også en udmærket screeningsmodel for potentielle medikamenter for slidgigt. Modellen bekræftede de gavnlige virkninger af glukokortikoider man tidligere har set på ledbrusk, men ikke på knogle. Udtømning af sulfat-glykosaminoglycaner (sGAG’s) fra brusk i begyndende slidgigt er ikke ensbetydende med udtømning af aggrecaner, da vi foreslår, at der er forskellige puljer af aggrecaner, der er følsomme over for forskellige typer af proteaser. Derudover afhænger rollerne for de endogene proteaser formentlig af det slidgigt-stadie man er i, da vi fandt forskellige frigivelsesmønstre af biokemiske markører i normalt brusk versus slidgigt brusk. Dette understreger betydningen af at udvikle forskellige behandlinger, der er specifikke for de forskellige stadier af slidgigt. 10
CHAPTER 1 Objectives CHAPTER 1: Objectives The aim of the PhD project was to gain further insight into the pathogenesis of osteoarthritis (OA) with respect to bone and cartilage, which are believed to be the primary tissues involved in joint turnover. In particular, the importance of the interaction between bone and cartilage was investigated to assess the importance of bone in the pathogenesis of OA. To this end, we wanted to develop a pre-clinical model that includes the two key tissues, subchondral bone and articular cartilage. Furthermore, as articular cartilage degradation is believed to be a hallmark of OA pathogenesis, we investigated the proteolytic processes of pathogenic cartilage in order to understand the OA-induced changes, which ultimately lead to cartilage loss. The PhD project had two main objectives: 1) The commercial objective. The first objective was to develop and validate a pre-clinical model system that allows investigation of whole tissue pathology in the pathogenesis of OA. This model should contain the three major cell types involved in the deterioration of joint structure, the osteoblasts, osteoclasts, and chondrocytes, including their cellular signalling processes (PAPER I). This model should allow testing of potential OA drugs in a more pathological relevant model. Thus, the effects of glucocorticoids as a potential drug for OA were tested in this model to evaluate the usefulness of the model and further to evaluate the effect of glucocorticoids on bone and cartilage cells (PAPER II). 2) The basic research objective. The second objective focused on the degradation of collagen type II and aggrecan in OA cartilage. We hypothesized that the loss of aggrecan in early and late OA was dependent on different proteases due to different molecular structures of the aggrecan. We expected to find different pools of aggrecan being degraded by appertaining proteases (so a specific protease should be targeted depending on the disease stage) (PAPER III). We also hypothesized that the ratio between endogenous proteases in OA cartilage, depends on the stage of the disease. Furthermore, we wanted to investigate if the biochemical markers were able to assess the different endogenous proteases in normal vs. OA cartilage (PAPER IV). 11
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 and 8: Contents Contents Abstract ........
Page 9 and 10: Abstract Abstract Osteoarthritis (O
Page 11: Sammendrag på dansk Sammendrag på
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
Page 63 and 64:
274 Cartilage 2(3) Figure 6. The an
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276 Cartilage 2(3) supports the inc
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278 Cartilage 2(3) release and rece
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CHAPTER 5 CHAPTER 5: PAPER II PAPER
Page 71 and 72:
leading to fragility fractures [12]
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after 1 week (Fig. 2F). The additio
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use a range of assays ranging from
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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 87 and 88:
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CHAPTER 7 CHAPTER 7: PAPER IV PAPER
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Introduction CHAPTER 7: PAPER IV Ca
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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
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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
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Appendix I 107
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Appendix I 109
Page 113 and 114:
Appendix I 111
Page 115:
Biochemical Markers of Joint Tissue
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