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Review
. 2019 Nov 22:38:246-263.
doi: 10.22203/eCM.v038a17.

Dexamethasone: chondroprotective corticosteroid or catabolic killer?

R Black, A J Grodzinsky  1
Affiliations
Review

Dexamethasone: chondroprotective corticosteroid or catabolic killer?

R Black et al. Eur Cell Mater. .

Abstract

While glucocorticoids have been used for over 50 years to treat rheumatoid and osteoarthritis pain, the prescription of glucocorticoids remains controversial because of potentially harmful side effects at the molecular, cellular and tissue levels. One member of the glucocorticoid family, dexamethasone (DEX) has recently been demonstrated to rescue cartilage matrix loss and chondrocyte viability in animal studies and cartilage explant models of tissue injury and post-traumatic osteoarthritis, suggesting the possibility of DEX as a disease-modifying drug if used appropriately. However, the literature on the effects of DEX on cartilage reveals conflicting results on the drug's safety, depending on the dose and duration of DEX exposure as well as the model system used. Overall, DEX has been shown to protect against arthritis-related changes in cartilage structure and function, including matrix loss, inflammation and cartilage viability. These beneficial effects are not always observed in model systems using initially healthy cartilage or isolated chondrocytes, where many studies have reported significant increases in chondrocyte apoptosis. It is crucially important to understand under what conditions DEX may be beneficial or harmful to cartilage and other joint tissues and to determine potential for safe use of this glucocorticoid in the clinic as a disease-modifying drug.

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Figures

Fig. 1.
Fig. 1.. Biological processes identified as being affected by DEX either in healthy or diseased cartilage in studies using in vivo models, cartilage explants or chondrocyte monoculture.
DEX affects matrix organisation at the level of both ECM and protease synthesis, although studies often disagree on the specific up- or down- regulation of ECM specific components. There is a consensus that, under arthritic stresses, DEX prevents the upregulation of protease synthesis, which can prevent matrix loss. However, at higher doses, in healthy cartilage, DEX may increase the rate of matrix degradation or the organisation of the matrix itself. This could be due to effects on matrix components and proteases or due to intracellular effects on metabolism and the production of ROS that activate autophagy and lead to significant cell death. Data from in vitro studies have suggested that DEX maintains cell viability under arthritic stress, which could be linked to a DEX-induced reduction in inflammatory cytokine synthesis. Alternatively, the metabolic processes that DEX dysregulates in healthy tissue could serve to rescue changes in those processes after the initiation of arthritis. While the induction of autophagy in healthy tissue could lead to chondrocyte death and subsequent matrix breakdown, autophagy is suppressed in arthritic contexts, so DEX could serve to rescue these cellular processes in a diseased state. It remains to be seen whether DEX inhibits proliferation under arthritic stress and what role this might play in disease progression and whether the phenomenon of DEX-induced reduction of proliferation in healthy cartilage is due to cells becoming quiescent or senescent. Each possibility would have a significantly different biological outcome on cartilage exposed to DEX for an extended time.
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