Identification of important interactions between subchondral bone ...

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CHAPTER 2: Introduction 2.3.4 Diagnostics - biochemical markers as a tool Several methods may be used to detect OA. X-ray detection is the golden standard method, where narrowing of the joint space indicates cartilage loss. Other ways to detect cartilage damage include arthroscopy and magnetic resonance imaging (MRI) 54,119 . However, OA is often diagnosed at late stages when the pain is unbearable for the patients, and the damages are too severe to repair. Today, many biochemical markers have been developed for the purpose of diagnosing the stage or degree of a specific disease. A biochemical marker is a single molecule or fragment of a molecule that is released into biological fluids (e.g. blood and urine) during tissue pathogenesis 54 . An increase in a specific biochemical marker indicates alterations of turnover, i.e., increased synthesis or breakdown 120 . Biochemical markers give a more accurate diagnosis of the severity of a disease for each patient, so that treatment could be designed specifically for the individual patient. Furthermore, the response to treatment or slow-down of the disease-progression can also be detected with these biochemical markers. OA is a disease affecting the whole joint and potential biochemical markers could originate from cartilage, bone, synovium, ligaments, tendons and muscles. However, the systemic levels from muscles, and some of the other tissues may exceed the small alterations seen from the OA-joint. At present, clinical studies indicate that different biochemical markers of cartilaginous matrix proteins may be useful to predict the early stages of cartilage damage and progression in OA. However, detection of OA by biochemical markers alone is not possible yet, as they measure systemic levels 54 . Nevertheless, the market for developing biochemical markers is increasing as it is possible to design more target-specific biochemical markers (e.g. neo-epitopes with post- translational modifications) or combine a specific selection of markers that represent one unique disease 121,122 . In OA, a central hallmark is the gradual destruction of articular cartilage and alterations in the subchondral bone 121 . The turnover of subchondral bone increases in early OA, which can be measured by increased formation and degradation of collagen type I (fig. 10A) and osteocalcin 123,124 . The resorption of collagen type I by osteoclasts is mediated by the protease, cathepsin K, which generates the neo-epitope, C-terminal telopeptide of collagen type I (CTX-I) 125,126,127 . However, studies have shown that both CTX-I and osteocalcin decrease in the body fluids of OA patients, indicating that overall bone turnover decreases in OA, whereas the increased turnover seen in subchondral bone is lost in systemic levels 128,129 . The turnover of cartilage is normally maintained by a balance between catabolic and anabolic processes; however, in the case of pathological matrix destruction, the rate of cartilage degradation exceeds the rate of formation, resulting in a net loss of cartilage matrix. During degradation of articular cartilage, MMPs and aggrecanases are considered the most important proteases for degradation of articular cartilage 130,131,132 . The key target proteins in cartilage is collagen type II and aggrecan (fig. 10B+C). Other important molecules in articular cartilage 30
CHAPTER 2: Introduction include cartilage oligomeric matrix protein (COMP), link protein and hyaluronic acid, which are out of the scope of the thesis. Fig. 10. Schematic illustration of proteolytic cleavage sites on collagen type I, collagen type II, and aggrecan. A) Collagen type I from bone. Formation of collagen type I is measured by PINP and PICP. Degradation of collagen type I by osteoclasts through cathepsin K cleavage is measured by CTX-I. B) Collagen type II from cartilage. Formation of collagen type II is measured by PIINP, PIIANP, and PIICP. Degradation of collagen type II by MMP cleavage is measured by CTX-II or CIIM. C) Aggrecan from cartilage. Aggrecan degradation is measured by the MMP-mediated marker, 342-G2, and the aggrecanase-mediated marker, 374-G2. The sGAGs (red lines) are also measureable as a marker, representing aggrecan turnover. The three figures were produced by Madsen, S.H. 31
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: CHAPTER 2: Introduction Cysteine pr
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
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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