Identification of important interactions between subchondral bone ...

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References for CHAPTER 7 (PAPER IV) 1 Archer C.W. and Francis-West P. The chondrocyte. Int J Biochem Cell Biol. 2003;35(4):401-404. 2 Rengel Y., Ospelt C., and Gay S. Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res Ther. 2007;9(5):221-21 3 Madsen S.H., Sumer E.U., Bay-Jensen A.C., Sondergaard B.C., Qvist P., and Karsdal M.A. Aggrecanase- and matrix metalloproteinasemediated aggrecan degradation is associated with different molecular characteristics of aggrecan and separated in time ex vivo. Biomarkers. 2010;15(3):266-276. 4 Karsdal M.A., Madsen S.H., Christiansen C., Henriksen K., Fosang A.J., and Sondergaard B.C. Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity. Arthritis Res Ther. 2008;10(3):R63- 5 Morko J.P., Soderstrom M., Saamanen A.M., Salminen H.J., and Vuorio E.I. Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis. Ann Rheum Dis. 2004;63(6):649-655. 6 Leeming D.J., Bay-Jensen A.C., Vassiliadis E., Larsen M.R., Henriksen K., and Karsdal M.A. Post-translational modifications of the extracellular matrix are key events in cancer progression: opportunities for biochemical marker development. Biomarkers. 2011;16(3):193-205. 7 Olsen A.K., Sondergaard B.C., Byrjalsen I., Tanko L.B., Christiansen C., Muller A., Hein G.E. et al. Anabolic and catabolic function of chondrocyte ex vivo is reflected by the metabolic processing of type II collagen. Osteoarthritis Cartilage. 2007;15(3):335-342. CHAPTER 7: PAPER IV 100 8 Sumer E.U., Sondergaard B.C., Rousseau J.C., Delmas P.D., Fosang A.J., Karsdal M.A., Christiansen C. et al. MMP and non-MMP mediated release of aggrecan and its fragments from articular cartilage: a comparative study of three different aggrecan and glycosaminoglycan assays. Osteoarthritis Cartilage. 2007;15(2):212-221. 9 Hui W., Rowan A.D., Richards C.D., and Cawston T.E. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum. 2003;48(12):3404-3418. 10 Mort J.S. and Billington C.J. Articular cartilage and changes in arthritis: matrix degradation. Arthritis Res. 2001;3(6):337-341. 11 Burrage P.S. and Brinckerhoff C.E. Molecular targets in osteoarthritis: metalloproteinases and their inhibitors. Curr Drug Targets. 2007;8(2):293-303. 12 Sondergaard B.C., Henriksen K., Wulf H., Oestergaard S., Schurigt U., Brauer R., Danielsen I. et al. Relative contribution of matrix metalloprotease and cysteine protease activities to cytokine-stimulated articular cartilage degradation. Osteoarthritis Cartilage. 2006;14(8):738-748. 13 Charni-Ben T.N., Desmarais S., Bay-Jensen A.C., Delaisse J.M., Percival M.D., and Garnero P. The type II collagen fragments Helix-II and CTX-II reveal different enzymatic pathways of human cartilage collagen degradation. Osteoarthritis Cartilage. 2008;16(10):1183-1191.
CHAPTER 8 CHAPTER 8: General discussion and conclusions General discussion and conclusions The main aim of this PhD project was to investigate the pathogenesis of OA with respect to bone and cartilage and the importance of the cellular interactions between these two tissues. One objective was to develop a pre-clinical model that can be used partly to investigate the interaction between osteoblasts, osteoclasts, and chondrocytes, and partly to test potential drugs for OA. This objective was successfully achieved by the development of the pre- clinical ex vivo model that included both subchondral bone and articular cartilage (fig. 13). Femur heads isolated from 3- to 12-week-old female mice were cultured as explants. These femur heads comprise a closed system, which are easy to isolate from their host without damaging the explants. Furthermore, the use of different ages of mice in the model allowed us to monitor changes simultaneously in both bone and cartilage, as the mice age. Hence, the femur head ex vivo model has advantages compared to the cartilage ex vivo model (only cartilage). However, the femur head model also has a disadvantage. Even though we characterized different ages of mice, we were not able to mimic human mature articular cartilage. Mice are short-lived (compared to human) and always in development, and therefore mimics immature cartilage. However, the immature cartilage in the murine femur heads contains hypertrophic chondrocytes, which are a hallmark of human OA, suggesting that this system could serve as an important disease model. It is debateable whether the hypertrophic chondrocytes from human OA are the same hypertrophic chondrocytes we see in the growth plate of growing mice. The established novel ex vivo femur head model was used as a screening model, to test prednisolone. Our results showed that prednisolone decreased cartilage degradation and decreased the turnover of bone (fig. 13). We also tested the effects of prednisolone and dexamethasone on bone or cartilage individually in other pre-clinical models, which confirmed that GCs protect cartilage, but not bone. Additionally, GCs did not appear to affect the lifespan and function of resting chondrocyte (fig. 13). These results suggest that the use of GC injections for OA is not preferable without considering the damaging effects on bone. Data obtained from this study also propose that the interaction between bone and cartilage is of less importance in regard to GC-treatment. Another objective was to gain greater insight into the proteolytic degradation processes of pathogenic cartilage since cartilage degradation and subsequently loss of the tissue is one of the hallmarks of the pathogenesis of OA. Loss of sGAGs from aggrecan is one of the first steps in the pathogenesis of OA. We found that there are different molecular structured pools of aggrecan that are degraded by different proteases (fig. 13), and we suggest that fully saturated aggrecan molecules, which are normally found in normal cartilage, are preferentially degraded by 101
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F A C U L T Y O F S C I E N C E U N
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Supervisors University of Copenhage
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Preface Preface The work presented
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Contents Contents Abstract ........
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Abstract Abstract Osteoarthritis (O
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Sammendrag på dansk Sammendrag på
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CHAPTER 1 Objectives CHAPTER 1: Obj
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CHAPTER 2 Introduction CHAPTER 2: I
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2.2 Biology of the joint CHAPTER 2:
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CHAPTER 2: Introduction Also osteob
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CHAPTER 2: Introduction follows nor
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CHAPTER 2: Introduction When the jo
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CHAPTER 2: Introduction Cartilage i
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2.3 The pathology of Osteoarthritis
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CHAPTER 2: Introduction number of a
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CHAPTER 2: Introduction Cysteine pr
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CHAPTER 2: Introduction include car
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2.4 The effect of Glucocorticoids C
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2.5 References for CHAPTER 2 1 WebM
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51 Lorenz H. and Richter W. Osteoar
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97 Nakamura H., Tanaka M., Masuko-H
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139 Garnero P., Ayral X., Rousseau
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CHAPTER 3 Overview of OA models CHA
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CHAPTER 3: Overview of OA models of
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3.3 Ex vivo controls CHAPTER 3: Ove
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Page 55 and 56: 266 Cartilage 2(3) therapy for oste
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Page 61 and 62: 272 Cartilage 2(3) Figure 5. Cytoki
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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]
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Page 115: Biochemical Markers of Joint Tissue
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