Although a substantial amount is known about the pathogenesis of osteoarthrosis, its aetiology and in particular the role that mechanical factors play, remains unclear. One particular hypothesis suggests that cartilage adapts mechanically so that it may transmit, without sustaining damage, the stresses to which it is predominantly subjected, and that damage to the cartilage is caused by infrequent high stresses in excess of the predominant level. As a corollary, it was suggested that highly stressed cartilage should be stiffer than lowly stressed cartilage. A survey of the mechanical properties of normal articular cartilage from unembalmed cadaveric knee and ankle joints was undertaken to test this hypothesis. For this purpose, a specially developed indentation test apparatus was commissioned. Tests of the machine's measurement capabilities indicate that coefficients of variation of 2.14% and 1.20% for indentation and cartilage thickness measurement could be expected. The maximum percentage errors in the calculated creep modulus value which could result from these typical measurement errors, were 4.2% and 2.9% respectively. Creep modulus values, calculated from these measurements, were used in topographical comparisons of cartilage stiffness. The stiffest areas of cartilage in the knee joint were the femoral condyles and areas of the tibia covered by the menisci. Cartilage on the patellar surfaces of the femur and in areas exposed by the menisci was significantly softer. Cartilage from the ankle joint was considerably stiffer than cartilage from the knee. Comparisons between the cartilage stiffness and levels of stress which act in the knee and ankle joints during normal ambulatory activity, showed the stiffest areas of cartilage to be subjected to the greater stresses. Correlations of averaged data values indicated a significant (p < 0.01) direct relationship between cartilage stiffness and stress. This relationship and the consistency with which osteoarthrotic lesions were found in areas subjected to damaging patterns of stress supported the hypothesis under examination. The lack of correlation found between the proteoglycan content and cartilage stiffness suggested that structural rather than compositional factors may be more important in influencing the compressive stiffness of normal articular cartilage.

Osteoarthritis (OA) is one of the most concerned diseases in the field of orthopaedics. During the process of this disease, articular cartilages are degenerated and worn out at the end stage, which create pain and disabilities to the patients. Although multiple mechanical and biochemical factors may initiate and/or enhance the progression of OA, alternation of biomechanical properties of articular cartilage is one of the products. There are several major components in articular cartilage; it is believed that each of their contribution cannot be entirely neglected. Superficial zone is mainly consisted with collagen and it was found that the biomechanical properties of this part of cartilage are also alternated significantly as a result of OA. Hence, degeneration of collagen network also occurs. Alternatively, osteoporosis (OP) is another common disease, which is associated to the decrease of bone mineral density; the effect of OP on articular cartilage is limited. In reverse, increasing bone mineral density in subchondral plate alters the loads distribution on articular cartilage and possibly leads to OA. This current study investigated the morphological and biomechanical properties of individual collagen fibrils extracted from OA, OP and healthy cartilages. A total of ten joint specimens were recruited, 3 OA joints were from 3 OA patients, 3 OP joints were from 3 OP patients, and 4 joints were from 2 healthy individuals. All cartilages were harvested from non weight-bearing zone, and average diameters were calculated from 350 fibrils’ measurements. In addition, 50 fibrils were randomly selected for nano-indentation under ambient condition. However, the representation of biomechanical properties tested at low humidity may be questionable. This current study also investigated the stiffness of hydrated fibrils. The results showed that the collagen fibrils extracted from OA cartilages were thinner than the ones extracted from OP and healthy cartilages. It was believe that the fibrillation and derangement of collagen network spread from superficial zone towards deeper zones. However, the number of thinner collagen fibrils increased in OA specimens could be the reason of the loss of larger fibrils and/or fragmentation occurred in the superficial zone, where contains thinner fibrils. The biomechanical tests showed that fibrils extracted from OA cartilages owned the highest elastic modulus, while the ones from OP had the lowest; significant differences were found between all groups when tested under ambient condition. Alternatively, the same pattern of results could also be found when hydrated fibrils were tested; however, due to the limited amount of samples, only the difference between OA and OP were considered significant. In addition, no individual difference was found; no significant difference between samples within each group could be observed. Since nano-indentations were performed at the center of each fibril, the elastic moduli measured represented the stiffness of the crosslinks and molecules within fibrils. Assuming the triple helix structure of collagen is relatively tough, the decrease of tensile modulus of superficial zone in OA cartilages could due to the changes of the crosslinks between fibrils in collagen network. / published_or_final_version / Orthopaedics and Traumatology / Master / Master of Philosophy

Asporin (ASPN) is a risk factor for osteoarthritis and intervertebral disc degeneration. Its expression increases with aging and degeneration. D14 (14 aspartate-repeat polymorphism) is the risk allele and D13 is the most common allele. In vitro studies suggest that Asporin functions as a negative regulator of Tgf-β signaling, an important stimulator of matrix formation in bone and cartilage. However, the in vivo role of Asporin in development or its involvement in the pathogenesis of degenerative cartilage diseases is unclear. Here, we use mouse as a model to study the impact of Asporin in the intervertebral discs of the spine. In wide type mice, we showed that Asporin is expressed and localized in the nucleus pulposus and annulus fibrosis of intervertebral discs, and the articular cartilage in knee joints. Furthermore, Asporin expressing cells in these tissues are active in Tgf-β signaling, suggesting a relationship between Asporin and Tgf-β signaling and a role in disc and articular joint maintenance. Using natural degeneration with aging, and models for induced degeneration in the mouse-tail discs, Asporin expression was shown to be up-regulated in nucleus pulposus and annulus fibrosis cells of degenerating intervertebral discs. These cells are also active in Tgf-β signaling supporting a potential relationship with the pathogenesis of disc degeneration. Transgenic mice overexpressing Asporin in cartilage tissues were generated to study this relationship and the impact on the differentiation and function of disc cells. Interestingly, overexpression of Asporin in the nucleus pulposus leads to enhanced production and deposition of extracellular matrix such as glycosaminoglycans, with concomitant changes in cell morphology, suggesting Asporin altered the extracellular matrix niche of resident nucleus pulposus cells. However, such changes are only observed in discs in the tail region but not in lumbar discs. We propose a relationship to mechanical loading as an environmental factor. Molecular analysis of transgene expressing cells showed Tgf-β signaling is active and its downstream target genes up-regulated. Furthermore, overexpression of Asporin enhances differentiation of notochordal-like cells (NCCs) in mouse nucleus pulposus toward the more mature nucleus pulposus cells (NPCs) and chondrocyte-like cells (CLCs) that are more abundant in the human nucleus pulposus and other larger animals that prompt to intervertebral disc degeneration. This study provided new insights into the function of Asporin in the pathogenesis of intervertebral disc degeneration. We proposed a model whereby Asporin, as a genetic risk factor, alters the extracellular environment of the nucleus pulposus, that in conjunction with environmental factors such as mechanical loading, enhances Tgf-β signaling, and consequentially, promotes the maturation of NCCs towards NPCs and CLCs, a hallmark of degenerative process proposed in human and other larger animal models. These transgenic mice provide the opportunity to better understand the relationship between genetic and environmental factors, and the molecular controls leading to the maturation process of NCCs in intervertebral disc degeneration. / published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

abstract / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Acetabular labral tears are associated with hip osteoarthritis. A current surgical treatment strategy for a torn labrum, labral resection, has recently shown poor patient outcomes with radiographic signs of osteoarthritis two-years post-operation. Since mechanical factors play a role in the etiology of osteoarthritis, identifying the mechanical role of the labrum may enhance current surgical treatment strategies. In this pilot study, we assessed the relationship between mean cartilage strain, maximum cartilage strain and the three-dimensional cartilage strain distribution in six human cadaver hips with various pathologic conditions of the labrum. We developed a novel technique of mapping cartilage strain using quantitative magnetic resonance imaging (qMRl). qMRl provides a non-invasive means of quantifying the cartilage strain distribution in the hip in three dimensions. Each specimen was assessed first with an intact labrum, then after surgically simulating a longitudinal peripheral labral tear, then after arthroscopically repairing the tear, and after labral resection. We validated the precision of the technique through use of an additional specimen which served as a control. To minimize motion artifact in the high-resolution MR images, we determined that 225 minutes was required for cartilage to reach a steady-state thickness under load. We also determined 16.5 hours was required for cartilage to recover to a steady-state unloaded thickness. The difference in mean and maximum cartilage strain when the labrum was repaired and resected was assessed using a paired t-test. We found that the resected group had an increased mean and maximum cartilage strain of 4% and 6%, respectively and the 3D cartilage strain distribution was elevated throughout the region of interest. When the condition of the intact labrum was compared to the torn labrum, we found no change in mean and maximum cartilage strain, and little obvious change in the 3D pattern of cartilage strain distribution. Based on our findings of increased cartilage strain after labral resection when compared to labral repair, we hypothesize that the labrum’s contribution of additional surface area assists in load distribution, which spares cartilage from excessive loads. We therefore recommend that the longitudinal peripheral torn labrum should not be resected if it is possible to be repaired, because in vivo, labral resection may create an environment with increased articular cartilage strain, which is thought to be associated with cartilage degeneration.

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