New Insights into the Pathobiology of Cartilage Degeneration
identified. The evidence reviewed here provides significant insight into the molecular mechanisms that underlie the cartilage breakdown that is characteristic of OA. Further support has been provided for previously identified therapeutic targets in cartilage tissue, while novel therapeutic targets have also been identified. Both hold great promise in advancing the understanding of the molecular events leading to OA.
Advances have also been made in the development of specific MMP13 inhibitors, with the overall goal being to eliminate side effects arising from earlier broad-spectrum inhibition. However, MMP13 has an important role in the physiologic turnover of the ECM in normal healthy cartilage tissue and, therefore, issues could still arise when considering complete and long-term inhibition of this proteinase.41,42
Furthermore,
MMP13 has a role in many important physiologic processes in other tissue types and, as a result, its inhibition could block normal physiologic functioning in these tissues.41,43
Future research should aim to address
the overall physiologic role of MMP13 and to make attempts at alleviating the possibility of adverse effects arising from its complete inhibition. These attempts could include the possibility of local administration of these compounds.
Less is currently known about the roles of ADAMTS-4 and ADAMTS-5 and, as a result, some questions remain. It is for this reason that future considerations should focus first on clarifying the aggrecanase activity
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that is important in human cartilage tissue compared with that in experimental animal models. As described for MMP13, completely blocking ADAMTS activity in cartilage and/or other tissues might have adverse effects. Nevertheless, these catabolic factors do hold promise as possible preventive measures for OA. This arises from the observation that aggrecanases have a role in early stages of disease progression.26,27,44
Preventing initial disease onset is the ideal approach as it eliminates the need for extensive treatment options.
Additionally, the identification of HIF-2α as a catabolic mediator in cartilage tissue suggests that there are still important factors to be considered in OA research. It seems probable that not all regulators of MMP13 and ADAMTS expression and function in cartilage have been identified, highlighting the importance of continued mechanistic studies and increasing the potential for the identification of additional therapeutic or preventive targets. Furthermore, there are additional catabolic factors (e.g. cathepsins and a multitude of other proteases, such as HtrA serine peptidase 1 [HTRA1]) for which important roles in cartilage tissue and, consequently, OA have been described.45–47
These
factors also need to be investigated to comprehend fully the molecular mechanisms leading to OA. It is evident that important progress has been made in elucidating the major catabolic factors of OA. Most importantly, these advances have provided evidence on which new and exciting future research in the field can be based. n
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