Identification of important interactions between subchondral bone ...

Future perspectives
CHAPTER 8: Future perspectives
One of the purposes for developing the femur head model was to investigate the cellular
interactions between bone and cartilage, although the GC-study did not provide evidence for
such an interaction between the two tissues. Evidently, this needs to be investigated in more
detail in the femur head model. In particular, it is not unlikely that some drugs may affect one
tissue directly, but impinge on another tissue indirectly, i.e., through the other tissue. If a
close coupling between cartilage and bone turnover exists, future treatment of OA most likely
need to restore or rebalance cellular communication in the joint. Otherwise, if the bone or
cartilage does not affect one another in the pathogenesis of OA, the optimal drug for OA
may be a cocktail of tissue-specific drugs.
Future studies could involve the
disassembly of the femur head explants in
bone and cartilage and compare fractions to
the intact femur head. In this way we may
be able to delineate how the drugs affect
bone and cartilage individually as compared
to the entire explants. In this regard, it would be critical to include femur heads from knock-
out mice, which lack the functional role of a specific cell type and/or signalling system in
order to investigate cellular crosstalk between the two tissues.
In line with our findings in the ex vivo femur head model, it is critical to investigate whether
hypertrophic chondrocytes in this model share similarities to cells in human OA. If the
hypertrophic chondrocytes have the exact same phenotype, it will increase the usefulness of
the ex vivo model in regard to mimicking human OA cartilage. If we find that the cells are not
exactly alike, we can use the ex vivo model to investigate the hypertrophic chondrocytes we
observe during development.
The present clinical use of intra-articular GC injections in OA knees, and the damaging
effects we find on bone by GCs in our study, highlights the importance of finding a
combination of drugs or a new GC, which do not have the detrimental effects on bone.
Thus, further studies using the novel femur head model could screen for potential drugs with
no detrimental effect on bone or cartilage.
Lastly, it is very important to understand the proteolytic processes of pathogenic cartilage in
order to developed new treatments for OA, which target the exact proteases that exert the
damaging effects at a given time during the pathogenesis of OA. We have already suggested
that it may be favourable to target aggrecanases in early OA and MMPs in later stages of OA.
However, more investigation on this topic is needed, especially in regard to investigate other
proteases than aggrecanases and MMPs, e.g., how important is the cathepsins in OA?
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