Identification of important interactions between subchondral bone ...

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CHAPTER 2: Introduction A schematic overview of the histopathological progression of OA is shown in fig. 9 65 . In very early OA, the superficial layer of cartilage is lost, the subchondral bone is getting denser, and blood vessels are penetrating the calcified cartilage. This affects the rest of the cartilage zones, which lose their organized matrix structures (fibrillation and loss of proteoglycans) and chondrocyte order (cluster formation). Simultaneously, the tidemark duplicates and is penetrated by blood vessels, and the subchondral bone increases in size and density as the cartilage is calcified and replaced by new bone. In moderate OA, the organization of the collagen network and chondrocyte column organization are lost and some of the chondrocytes have differentiated into hypertrophic chondrocytes. The subchondral bone still increases in size and penetrate the cartilage compartment. In late OA, only some parts of the deep zone of cartilage is left and the subchondral bone has increased in size and intermingled with cartilage (calcified zone has disappeared). At the end stage OA, the cartilage is lost and the subchondral bone is exposed. This may lead to synthesis of woven bone, which results in deformation of the joint. Fig. 9. The pathological development of OA. The progression of OA is shown from the healthy stage to the end stage of the disease, with focus on the matrix structure, cell number and phenotype, and ratio between cartilage and subchondral bone. This figure illustrates the simultaneous processes of both bone and cartilage in the pathogenesis of OA. Figure adapted from Bay-Jensen et al. 65 . 2.3.1 A chondrocyte is not just a chondrocyte Most people develop OA in later stages of life. One of the main reasons lies within the adult articular chondrocytes, which are ultimately responsible for remodelling and maintaining the health of the cartilage, even though these cells possess only little regenerative capacity. Research has shown that chondrocyte proliferation is rare in normal adult cartilage, and a reduction in the 26
CHAPTER 2: Introduction number of active chondrocytes occurs with age along with a reduction in their response to anabolic factors. Therefore, the increased loss of chondrocytes during the later stages of life and thus the increasing lack of regeneration eventually result in damaged cartilage and the development of OA 66,67,68,69,70 . However, in the pathogenesis of OA, chondrocytes proliferate to form multiple cells within a chondron, which is a pivotal change from normal cartilage, where more than 2–3 cells are unusual, even in the elderly 71 . These clusters of chondrocytes in OA are not to be mistaken for the chondrocytes in healthy adult cartilage, as chondrocytes can change into different phenotypes during the progression of OA: An anabolic phenotype that expresses ECM proteins; e.g. collagen type II and aggrecan 72 A catabolic phenotype that expresses proteolytic enzymes that degrade the ECM 11,73,74 A Hypertrophic phenotype that expresses collagen type X before it undergoes apoptosis 75 A dedifferentiated phenotype that expresses collagen type I (often in repair areas after damage 76,77 A chondroblastic phenotype that expresses fetal type IIA collagen and type III collagen 78 The differentiation of chondrocytes into these phenotypes probably occurs due to a “panic- attack” from the insufficient adult chondrocytes, who cannot keep up with the repair mechanisms of damaged cartilage. As a solution, the very productive phenotypes seen from the skeletal development are starting to emerge. Evidence of phenotypic change for chondrocytes is reflected in the presence of collagens not normally found in adult articular cartilage. As an example, the splice-variant of collagen type II, type IIA (which is normally expressed by chondroblasts during development) is re-expressed in early and late-stage OA 78 . Other indicators of a potential reversion of the cells to an earlier developmental phenotype are the hypertrophic chondrocyte marker, collagen type X 79 as well as the general increased production of proteins, proteinases, growth factors, cytokines, and other inflammatory mediators by more active/productive chondrocytes 80,81,82 . The adult articular chondrocytes normally maintain the cartilage homeostasis with a low turnover of matrix constituents. In OA, the chondrocytes attempt to recapitulate phenotypes of early stages of cartilage development, whose rate of synthesis of matrix constituents are faster. However, and unfortunately, the original cartilage cannot be replicated. 27
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: 2.3 The pathology of Osteoarthritis
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
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
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CHAPTER 6 CHAPTER 6: PAPER III PAPE
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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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