Abstract
Osteoarthritis (OA) is a type of degenerative arthritis that limits daily activity and quality of life for more than 10% of the people worldwide. Having a better insight into the mechanisms of OA pathology is a key to better diagnostic strategies and improved therapies. OA patients experience different stages of
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disease progressing from a pre-OA to early and eventually end-stage OA. Irreversible structural damage is mainly detectable in the progressed stages of OA at tissue level, while early degradations are initiated at a small molecular-scale from the pre-OA stage. This underscores the importance of detecting the early signs of OA especially on a molecular-scale. Articular cartilage is a highly specialized load-bearing tissue that reduces friction and distributes forces over the underlying bone. Articular cartilage has a hierarchical structural architecture which mainly consists of proteins and polysaccharides such as type II collagen and proteoglycans that make up the extracellular matrix (ECM), and chondrocytes. Chondrocytes are responsible for tissue homeostasis, which is an outcome of a series of phenomena that exists in the cartilage matrix. Mechanical properties (especially elasticity) can be considered as a key determinant of cartilage health. This PhD dissertation aims to provide detailed knowledge of mechanobiological mechanisms contributing to the age- and overload-related deterioration of articular cartilage. To address the general hypothesis, we applied a set of multi-scale biomechanics experimental tools on articular cartilage of various species. We sought to determine the mechanical contributions of its main components, such as collagen fibers and proteoglycans, especially at the superficial zone where the osteoarthritis-related biomechanical abnormalities likely initiate. The obtained indentation-based mechanical properties from the molecular (Atomic Force Microscopy) to more tissue level (nano-indenter), together revealed the contribution of cartilage specific components to its overall mechanics. We also found that the cartilage stiffness as determined from indentation tests is highly dependent on indentation and indenter characteristics has a very high spatial variability, necessitating a large number of indentation tests to provide a representative characteristic of the mechanical response of cartilage under investigation. Subsequently, we investigated the effect of mechanical loading on the knee joint and the resulting cartilage and bone adaptation at both cell and tissue levels, in an experiment with rats. Our observations proved the dynamic nature of bone turnover which continuously reacts to forces as well as cartilage/chondrocyte mechano-sensitive responses to mechanical stimuli. Then, we analyzed artificially induced ‘age’-related changes regarding advanced glycation in both equine and rodent articular cartilage from the mechanobiological viewpoint. Micro- and nano-scale indentation experiments indicate that AGE crosslinks enhance cartilage overall stiffness, which is associated with increased cross-linking density of the collagen fibers. In addition, we showed that it is possible to tailor the efficiency of AGEs-related cross-linking by manipulation of the collagen fiber pre-stress induced via osmotic pressure.
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