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