Identification of important interactions between subchondral bone ...

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CHAPTER 2: Introduction Bone is a specialized tissue, which together with cartilage make up the human skeleton. The bones have three main functions; 1) providing mechanical support for the whole body and acting as muscle attachment for locomotion, 2) providing protective shields for the vital organs and the bone marrow, and 3) providing a reserve for ions, mainly calcium and phosphate, and for growth factors and cytokines 15,16 . There are several subtypes of bones; long bone, flat bones, short bones and irregular bones 17 , of which only long bones - e.g. femur and tibia, which constitute the knee - will be discussed further in this thesis. Long bones are developed by endochondral ossification as shown in fig. 2A 18 . This whole process starts with a condensation of mesenchymal cells to form the cartilage anlage of the future bone. The mesenchymal cells further proliferate and differentiate into chondroblasts. The chondroblasts produce a cartilaginous matrix, where the predominant collagen is collagen type II. The chondroblasts become progressively embedded within their own matrix, where they lie within lacunae, and they are then called chondrocytes (the only cell type in articular cartilage). Eventually, the chondrocytes may further differentiate into hypertrophic chondrocytes whereby the cartilage becomes calcified before the hypertrophic chondrocytes undergo apoptosis and then disappear from the lacunae. This generates the primary ossification-centre, which splits into two opposite growth plates that moves from the centre of the long bone, towards the ends. At this stage of bone development, the blood vessels penetrate the calcified matrix supplying osteoclast precursors. Differentiated osteoclasts (bone resorbing cells) use the lacunas in the calcified cartilage matrix as templates to initiate resorption. Fig. 2. Development of long bone by endochondral ossification. Schematic diagram showing the initial stages of endochondral ossification. A) Endochondral ossification is initiated from accumulated mesenchymal cells, which continue to differentiate and starts forming the primary, and then later the two secondary ossification centres. Trabecular bone is present after several cycles of remodelling 16 . B) The growth plate between the epiphysis and diaphysis is enlarged and divided in the different zones. The growth plate demonstrates the different stages of chondrocyte differentiation involved in endochondral bone formation. The figure was produced by Madsen, S.H. 16
CHAPTER 2: Introduction Also osteoblasts (bone forming cells) arrive with the bloodstream and form a layer of woven bone on top of the remaining cartilage. The septae of calcified cartilage separating the lacunae are first resorbed by osteoclasts, while the remaining septae that extend into the diaphysis are used for osteoblasts to deposit bone matrix, resulting in the vascular bone marrow cavity (fig. 2A) 19 . The bone continues to grow through both the growth plates in appertaining epiphyses. In the growth plate (see fig. 2B) resting chondrocytes resume proliferation organized in columns toward the diaphysis and then mature into hypertrophic cells that express specific genes, such as collagen type X, and calcify the matrix. After apoptosis of the hypertrophic chondrocytes, the calcified matrix is resorbed by osteoclasts followed by bone deposit by osteoblasts. This process is known as the bone modelling process, where bone resorption and formation occur independently of each other. This modelling continues as long as needed, and eventually, secondary ossification-centres begin to form at the epiphyseal ends of the long bone. At the end of human adolescents, the proliferation of chondrocytes in the growth plate slows down and eventually stops. The continuous replacement of cartilage by bone results in the obliteration of the growth plate. Only articular cartilage remains. During primary bone formation, woven bone structures are first formed, which comprise some amount of calcified cartilage. The woven bone will later be replaced by the more robust lamellar bone without calcified cartilage, during remodelling of the bone matrix (described in section 2.2.3), which is a different process than the modelling process. Mineralization of articular cartilage and its replacement by bone continues in the adult, however, at a much reduced rate than in growing bone 19,20 . 2.2.2 Adult bone - macroscopic and microscopic organization After a long bone is fully developed, it has two epiphyses covered with a layer of articular cartilage, a cylindrical hollow portion in the middle called the diaphysis, and a transition zone between them called the metaphysis (see fig. 3) 16 . The long bone is divided in two types of structural bone (fig. 3): I) The external part of the long bone is formed by a thick and dense layer of calcified tissue called the cortex, which encloses the medullary cavity where the hematopoietic bone marrow is housed 17 . II) Toward the metaphysis and the epiphysis, the cortex becomes progressively thinner and the internal space is filled with a network of thin, calcified trabecular bone. The spaces enclosed by these thin trabeculae are also filled with hematopoietic bone marrow and are continuous with the diaphyseal medullary cavity 17 . 17
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: 2.2 Biology of the joint CHAPTER 2:
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
Page 65 and 66: 276 Cartilage 2(3) supports the inc
Page 67 and 68: 278 Cartilage 2(3) release and rece
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CHAPTER 5 CHAPTER 5: PAPER II PAPER
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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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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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