Identification of important interactions between subchondral bone ...

CHAPTER 1
Objectives
CHAPTER 1: Objectives
The aim of the PhD project was to gain further insight into the pathogenesis of osteoarthritis
(OA) with respect to bone and cartilage, which are believed to be the primary tissues involved in
joint turnover. In particular, the importance of the interaction between bone and cartilage was
investigated to assess the importance of bone in the pathogenesis of OA. To this end, we wanted
to develop a pre-clinical model that includes the two key tissues, subchondral bone and articular
cartilage. Furthermore, as articular cartilage degradation is believed to be a hallmark of OA
pathogenesis, we investigated the proteolytic processes of pathogenic cartilage in order to
understand the OA-induced changes, which ultimately lead to cartilage loss.
The PhD project had two main objectives:
1) The commercial objective.
The first objective was to develop and validate a pre-clinical model system that allows
investigation of whole tissue pathology in the pathogenesis of OA. This model should contain
the three major cell types involved in the deterioration of joint structure, the osteoblasts,
osteoclasts, and chondrocytes, including their cellular signalling processes (PAPER I). This model
should allow testing of potential OA drugs in a more pathological relevant model. Thus, the
effects of glucocorticoids as a potential drug for OA were tested in this model to evaluate the
usefulness of the model and further to evaluate the effect of glucocorticoids on bone and
cartilage cells (PAPER II).
2) The basic research objective.
The second objective focused on the degradation of collagen type II and aggrecan in OA
cartilage. We hypothesized that the loss of aggrecan in early and late OA was dependent on
different proteases due to different molecular structures of the aggrecan. We expected to find
different pools of aggrecan being degraded by appertaining proteases (so a specific protease
should be targeted depending on the disease stage) (PAPER III). We also hypothesized that the
ratio between endogenous proteases in OA cartilage, depends on the stage of the disease.
Furthermore, we wanted to investigate if the biochemical markers were able to assess the
different endogenous proteases in normal vs. OA cartilage (PAPER IV).
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