Identification of important interactions between subchondral bone ...

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CHAPTER 2: Introduction The degradation and formation of collagen type II can be measured by several biochemical markers 133 , but the present thesis mainly focuses on the MMP-mediated biochemical markers; e.g. C-terminal telopeptide of collagen type II (CTX-II) 129,134 and the novel CIIM 135 (fig. 10B). Several studies have shown that the CTX-II level is elevated in OA patients and in cartilage degradation from ex vivo-cultures 134,136,137 . It remains to be resolved whether this increase in CTX-II results from degradation of pre-existing collagen type II or newly synthesized collagen 138,139 . The formation markers of collagen type II, PIINP or PIIANP can in combination with the CTX-II or CIIM markers provide a more complete understanding of the turnover-actions. PIIANP is an attractive formation marker for OA-cartilage as it is an indicator of expression of the fetal form of collagen type IIA, which is re-expressed by OA chondrocytes 78,140 . The formation markers, PIINP and PIIANP, are normally suppressed in OA patients 141,142 . Another study has shown that PIIANP levels are increased in OA patients 138 , suggesting that PIIANP values are not always consistent. The degradation of aggrecan has attracted attention as a biochemical marker, as aggrecan degradation occurs early in OA and prior to collagen degradation 143 . Both MMP and aggrecanase-cleaved aggrecan fragments have been identified in synovial fluid 144 . The concentration of aggrecanase-mediated fragments (374-G2) dominated the MMP-mediated fragments (342-G2) in cartilage degradation ex vivo 144,145 , suggesting that the major mediators of aggrecan loss in OA are the aggrecanases. Biochemical markers are key-tools used to investigate the hypotheses in this thesis. 32
2.4 The effect of Glucocorticoids CHAPTER 2: Introduction Glucocorticoids (GCs) belongs to a class of steroid hormones that bind to the glucocorticoid receptor (GR). This receptor is present in almost every vertebrate animal cell and activation of GRs initiate an up-regulation of the expression of anti-inflammatory proteins and represses the expression of pro-inflammatory proteins 146 . Consequently, GCs have potent anti-inflammatory and immunosuppressive properties and are thus part of the feedback mechanism in the immune system that decreases the inflammation 147,148 . Therefore, GCs are used as drugs to treat inflammatory conditions such as arthritis (e.g. rheumatoid arthritis), dermatitis, and diseases that are caused by an overactive immune system (allergies, asthma, and autoimmune diseases) (Table 1) 146,148 . GCs are also administered as post-transplant immunosuppressants to prevent any acute transplant rejection and graft-versus-host disease. However, they do not prevent an infection and they also inhibit later reparative processes 146 . Treatment with GCs has many diverse effects, including potentially harmful side effects (Table 1) 146 . Excessive GC levels resulting from administration as a drug affect many systems, including inhibition of bone formation, suppression of calcium absorption and delayed wound healing 148 . With respect to OA, intra-articular injections of GCs appear to have a reducing effect on inflammation and pain 149 . Unfortunately, prolonged GC therapy results in GC-induced osteoporosis 150 . Thus, to treat OA, GCs without detrimental effects on bone are needed. The major endogenous GC in humans is cortisol, which was first used therapeutically for rheumatoid arthritis by Hench and co-workers in 1949 151 . Since then, a large number of synthetic compounds with GC activity have been developed for therapeutic use. They differ in pharmacokinetics and pharmacodynamics 152 . The potencies and effects of some of the synthetic glucocorticoids used for treatment are described in Table 1. Table 1. Synthetic glucocorticoids and their effects/side-effects. Most of the synthetic glucocorticoids have the same general effect (anti-inflammatory and immunosuppressive effects), but the potency and specificity for certain diseases vary 153,152 . 33
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 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: CHAPTER 2: Introduction include car
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
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
Page 75 and 76: use a range of assays ranging from
Page 77 and 78: still some controversy regarding th
Page 79 and 80: CHAPTER 6 CHAPTER 6: PAPER III PAPE
Page 81 and 82: Biomarkers Downloaded from informah
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Biomarkers Downloaded from informah
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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
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Appendix I 111
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Biochemical Markers of Joint Tissue
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