Mechanisms of osteoarthritis : interrelationships between bone and cartilage.

Abstract

Osteoarthritis (OA) is a progressive joint disease and a common cause of disability. OA is characterised by loss of articular cartilage, subchondral bone sclerosis, cysts, and osteophyte formation. Increased subchondral bone remodelling plays an important role in the pathophysiology of OA and is associated with disease progression. It is known that Osteoprotegerin (OPG), receptor activator of nuclear factor kappa b (RANK) and its ligand RANKL tightly control bone remodelling. In addition, RANK, RANKL and OPG gene expression has been shown to be dysregulated in human OA subchondral bone. Commonly OA is diagnosed at advanced stages, which makes it difficult to study the initiating events in the human disease. Animal models of OA are of considerable importance to study the progressive changes in OA, and to evaluate suitable OA drugs. Alendronate (ALN) is a potent bone resorption inhibitor and clinical trials using bisphosphonates to treat OA have yielded mixed results. This suggests that the effects of bisphosphonates may or may not be beneficial depending on the stage of OA progression. The first aim of this thesis was to characterise the temporal structural changes of tibial articular cartilage and subchondral bone in a low-dose MIA-induced OA rat model. The results from micro-CT analysis showed that the tibiae of the MIA-injected knees had significant bone loss at 2 weeks (early OA), followed by increased bone volume, trabecular thickness and separation at 6 weeks (intermediate OA) and 10 weeks (advanced OA). Micro-CT images revealed subchondral bone sclerosis, cysts, and osteophyte formation at 6 and 10 weeks. Histology revealed progressive cartilage degradation characteristic of the human disease. The second aim of this thesis was to study the effect of ALN treatment initiated at day 0 (pre-emptive), week 2 (early treatment), and week 6 (delayed treatment) in a low-dose MIA rat model. To address the second aim the efficacy of ALN was tested on cartilage degradation, subchondral bone remodelling, and joint discomfort observed in this animal model. The study demonstrated that pre-emptive ALN treatment preserved subchondral trabecular bone microarchitecture, decreased bone turnover, prevented joint discomfort, and offered moderate chondroprotection. Early and delayed ALN treatment prevented loss of trabeculae and decreased bone turnover but did not have any identified effect on cartilage. Finally, the RANK, RANKL, OPG gene expression in OA was characterised in a lowdose MIA rat model. The effect of ALN treatment on subchondral bone RANK, RANKL, and OPG gene expression at 2, 6, and 10 weeks after OA induction was assessed. This study showed that the RANKL and OPG gene expression was dysregulated in this animal model. In addition, the efficacy of ALN on early subchondral bone changes appears to occur through the modulation of RANKL and OPG gene expression. Collectively, these findings demonstrate that the low-dose MIA rat model closely mimics the pathological features of progressive human OA disease. Moreover, this animal model showed a clear relationship between the cartilage damage and subchondral bone changes. ALN treatment preserved subchondral trabecular bone microarchitecture and decreased bone turnover. In addition, ALN prevented RANKL and OPG gene dysregulation in OA subchondral bone. Normalising subchondral bone remodelling offers an optimal treatment option and future drug intervention studies focusing on subchondral bone would provide improved treatment options for OA.