Theses Doctoral

Microstructural and biomechanical bone adaptations in a longitudinal study of guinea pig osteoarthritis and simulated disease progression

Sykes, Andreea Teodora Dinescu

Osteoarthritis (OA) is a prevalent joint disease without a cure and leading cause of disability worldwide. Knee OA is the most common and expected to increase with a growing, aging population. OA is clinically diagnosed by the measure of joint space narrowing on a radiograph and pain scores, though OA is now known to be a disease of the whole joint and characterized by cartilage degradation, subchondral bone sclerosis, synovitis, meniscal erosion and inflammation. There are currently no disease-modifying therapies because the pathogenesis and progression of these events are unknown. Recent studies have demonstrated the importance of subchondral bone in OA initiation. Using an advanced imaging technique called individual trabecula segmentation (ITS) to decompose the trabecular network into individual plates and rods, subtle microstructural changes were identified beneath both intact and damaged cartilage in human OA. These findings were also observed during OA initiation before cartilage changes in a model of guinea pig OA. The aims of this study were to further investigate these bone microstructural changes and investigate how they affect the mechanical properties of trabecular bone and overlying articular cartilage.

In the first aim, the Dunkin-Hartley guinea pig model of spontaneous OA was used to quantify ITS-based trabecular microstructural changes in the knee joint during OA initiation in both a longitudinal and cross-sectional analysis. In the longitudinal study, microstructural changes in the subchondral bone were quantified from μCT images and voxel-based modeling and remodeling. In the cross-sectional study, structural, biomechanical and biochemical properties of articular cartilage, subchondral bone plate and trabecular bone were analyzed. In both the longitudinal and cross-sectional analyses, there was a trend towards increased thickness, a significant decrease in porosity, and increased mineralization in the subchondral bone plate. There was an increase in the plate-to-rod (PR) ratio due to a loss of trabecular rods, an increase of trabecular plates, and thickening of trabecular plates before any visible histological changes in the cartilage. Voxel-based bone modeling and remodeling analysis confirmed that there was a loss of rods and not merely that the rods were turning into plates.

This confirmed our hypothesis that trabecular rod loss precedes cartilage damage and could be a potential therapeutic target. There was a trend towards an increase in the apparent elastic modulus of bone followed by a reduction in the modulus, with the stiffest and most drastic reduction in the medial tibial plateau, which coincided with cartilage fibrillations and a trend towards reduction in the cartilage aggregate modulus. The tissue-level mechanical properties of the trabecular bone are due to both microstructural changes in the trabecular network and material changes in the tissue modulus. Micro-indentation of the trabecular bone revealed a trend towards an increase in the tissue modulus in the medial tibial plateau, followed by a reduction in the tissue modulus. This suggested that during OA progression, there is rapid formation of lower-quality bone with a reduced capacity to mechanically support the joint. In summary, there were structural and mechanical bone changes observed before histological, mechanical or biochemical changes in the articular cartilage.

In the second aim, a mechanically-driven subchondral bone computational model was developed. Under equilibrium conditions to simulate aging, there was no change in bone volume fraction and there was a shift from plate-like to rod-like trabecula. There was a slight decrease in the apparent elastic modulus of the bone. Under increased applied strain to simulate the effects of obesity, there was an increase in bone volume fraction, due to both a rod loss and plate thickening. This change came from rod loss, rods thickening and becoming plates, as well as rods and plates merging together. These microstructural changes caused an increase in the apparent elastic modulus of bone. This study demonstrated that the microstructural changes observed in OA can be simulated by increasing the applied strain.

Taken together, these studies demonstrate how bone microstructural changes in OA initiation affect the mechanical integrity of the subchondral bone and could cause abnormal stress distributions in the overlying cartilage and promote cartilage degradation. Therapies that prevent bone loss, like bisphosphonates, could be investigated to prevent this initial rod loss as a means of potentially slowing or reversing OA progression.


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More About This Work

Academic Units
Biomedical Engineering
Thesis Advisors
Guo, Xiang-Dong Edward
Ph.D., Columbia University
Published Here
September 27, 2023