Investigating the impact of tibial malalignment in OA development in a mechanically induced rodent osteoarthritis model
File(s)
Author(s)
Xu, Luyang (Leah)
Type
Thesis or dissertation
Abstract
This study aimed to investigate the impact of tibial malalignment, a strong mechanical factor that occurs spontaneously, on the initiation and development of osteoarthritis (OA) in a rodent model. Different degrees of malalignment were induced to create a model of chronic primary OA resulting from natural chronic overloading, with varying levels of severity. This mechanically-induced model was then used to characterize OA in both early and progressive stages through histological cartilage degradation, radiographic structural changes, gait patterns, and cytokine levels, alongside pharmacological treatment effects.
Histological analyses revealed distinct changes in OA cartilage in response to tibial malalignment. Treatment with autologous protein solution (APS) resulted in cartilage that more closely resembled healthy tissue, while bone morphogenetic protein (BMP) treatment stimulated repair but also promoted chondrophyte formation. Micro-CT analysis highlighted adaptive changes in subchondral bone to accommodate the new mechanical demands of OA, including increased subchondral bone plate thickness, decreased trabecular bone volume fraction and trabecular bone thickness, increased trabecular spacing, and osteophyte formation. While BMP treatment showed potential for subchondral bone repair, it also appeared to stimulate osteophyte growth.
Gait analysis proved to be an effective method for distinguishing between different OA states and assessing recovery following pharmacological treatments. Key variables across all discrimination models for both limbs included Paw Area at Peak Stance (indicating weight support) and Max dA/dT (indicating gait coordination), which highlighted compensatory changes in the contralateral limb. Untargeted LFQ-MS proteomics reveals key biological processes such as collagen formation and degradation, endochondral ossification, and metabolic responses involved in OA pathogenesis.
This study successfully linked histological, structural, gait, and molecular changes to OA pathogenesis. It suggests that although early treatment with BMP and APS can mitigate OA progression by modulating these processes through different pathways, they cannot fully halt the progression if mechanical abnormalities persist.
Histological analyses revealed distinct changes in OA cartilage in response to tibial malalignment. Treatment with autologous protein solution (APS) resulted in cartilage that more closely resembled healthy tissue, while bone morphogenetic protein (BMP) treatment stimulated repair but also promoted chondrophyte formation. Micro-CT analysis highlighted adaptive changes in subchondral bone to accommodate the new mechanical demands of OA, including increased subchondral bone plate thickness, decreased trabecular bone volume fraction and trabecular bone thickness, increased trabecular spacing, and osteophyte formation. While BMP treatment showed potential for subchondral bone repair, it also appeared to stimulate osteophyte growth.
Gait analysis proved to be an effective method for distinguishing between different OA states and assessing recovery following pharmacological treatments. Key variables across all discrimination models for both limbs included Paw Area at Peak Stance (indicating weight support) and Max dA/dT (indicating gait coordination), which highlighted compensatory changes in the contralateral limb. Untargeted LFQ-MS proteomics reveals key biological processes such as collagen formation and degradation, endochondral ossification, and metabolic responses involved in OA pathogenesis.
This study successfully linked histological, structural, gait, and molecular changes to OA pathogenesis. It suggests that although early treatment with BMP and APS can mitigate OA progression by modulating these processes through different pathways, they cannot fully halt the progression if mechanical abnormalities persist.
Version
Open Access
Date Issued
2024-04-04
Date Awarded
2024-09-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Bull, Anthony
Sponsor
Royal British Legion
Grant Number
BMPF-PS3013
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)