Suzi Høgh Madsen:
Identification of important interactions between subchondral bone turnover and cartilage degradation in the pathogenesis of osteoarthritis

Date: 15-11-2011    Supervisor: Søren Tvorup Christensen

Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability, with prevalence increasing with age. At present there are no structure modifying treatments accepted by the Food and Drug Administration (FDA), emphasizing the need for understanding the pathogenic processes leading to OA. OA is a complex disease of the entire joint, including bone, cartilage and the synovium, and it is characterized by the progressive degradation of articular cartilage, mild synovial inflammation, and alterations of the subchondral bone. Currently, it is not clear whether the pathogenesis of OA originates in the bone or cartilage compartment, and little is still known on how these compartments drive disease progression. An increased amount of evidence suggests a strong coupling between the subchondral bone and the articular cartilage turnover, with pathological processes occurring simultaneously in both compartments. Therefore, an optimal intervention strategy for OA likely includes targeting both bone and cartilage compartments.

The aim of the thesis was to investigate the pathogenesis of OA with respect to bone and cartilage, and the importance of the interaction between the two tissues. Understanding the interactions between osteoclasts, osteoblast and chondrocytes may be essential for the development of future treatments for OA.

Before the launch of this thesis, there were no validated pre-clinical models that allowed investigation of whole tissue pathology of OA in one single system, which combined the metabolism of the implicated cell types. Thus, the present thesis focused on the development and characterization of a novel murine ex vivo femur head model, comprising the three major cell types involved in the deterioration of joint structure; the osteoblasts, osteoclasts, and chondrocytes. We have established the ex vivo femur head model with positive and negative controls, which allow the investigation of the interaction between bone and cartilage. Furthermore, by using the novel ex vivo model and other pre-clinical models, we evaluated the effect of glucocorticoids on bone and cartilage and found that the effect of glucocorticoids highly depend on the activation and differential stage of the cell targeted in the joint.

The thesis also studied the degradation processes of cartilage, focusing on the two predominant proteins; aggrecan and collagen type II. We investigated the molecular differences between matrix metalloproteinase- and aggrecanase-mediated aggrecan degradation as a consequence of their distinct time-dependent degradation profiles. We found that the aggrecan molecule may be divided into two different protease-specific pools. Furthermore, we investigated the differences between normal and OA cartilage with respect to endogenous proteases (assessed by biochemical markers) and found that the degradation markers are released in part by different proteolytic pathways.