Intra-articular dexamethasone to inhibit the development of post-traumatic osteoarthritis

Abstract

Injury to the joint provokes a number of local pathophysiological changes, including synthesis of inflammatory cytokines, death of chondrocytes, breakdown of the extra-cellular matrix of cartilage, and reduced synthesis of matrix macromolecules. These processes combine to engender the subsequent development of post-traumatic osteoarthritis (PTOA). To prevent this from happening, it is necessary to inhibit these disparate responses to injury; given their heterogeneity, this is challenging. However, dexamethasone has the necessary pleiotropic properties required of a drug for this purpose. Using in vitro models, we have shown that low doses of dexamethasone sustain the synthesis of cartilage proteoglycans while inhibiting their breakdown after injurious compression in the presence or absence of inflammatory cytokines. Under these conditions, dexamethasone is non-toxic and maintains the viability of chondrocytes exposed chronically to such cytokines as interleukin (IL) -1, IL-6, and tumor necrosis factor-α. Moreover, the anti-inflammatory properties of dexamethasone have been appreciated for decades. In view of this information, we have initiated a pilot clinical study to determine whether a single, intra-articular injection of dexamethasone into the wrist shows promise in preventing PTOA after intra-articular fracture of the distal radius.

Clinical significance: Suppressing the various etiopathophysiological responses to injury in the joint is an attractive strategy for lowering the clinical burden of PTOA. The intra-articular administration of dexamethasone soon after injury offers a simple and inexpensive means of accomplishing this. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:406-411, 2017.

Keywords: cartilage; hand and wrist; pathophysiology; synovium and osteoarthritis; trauma.

Figure 1. Dose-dependent effects of dexamethasone on GAG loss and GAG synthesis in cartilage explants exposed to TNF-α

Cartilage samples were maintained in serum-free medium containing low-glucose DMEM, 10 mM HEPES buffer supplemented with 1% ITS: insulin (10 μg)-transferrin (5.5 μg/ml) – selenium (5 ng/ml). Dexamethasone and TNF-α were added at the indicated concentrations, for six days. Panel A: Effects on GAG loss. Panel B: Effects on GAG synthesis. Values given are means ± SEM, n=5. * = p<0.05 difference from untreated cells. From reference , with permission

Figure 2. Effect of dexamethasone on GAG loss and GAG synthesis in cartilage explants exposed to combinations of mechanical injury and cytokines

Cartilage samples were maintained in serum-free medium containing low-glucose DMEM, 10 mM HEPES buffer supplemented with 1% ITS: insulin (10 μg)-transferrin (5.5 μg/ml) – selenium (5 ng/ml). Dexamethasone and TNF-α were added at the indicated concentrations, for six days. Panel A: Effects on GAG loss. Panel B: Effects on GAG synthesis. Values given are means ± SEM, n=5. * = p<0.05. From reference , with permission

Figure 3. Effect of dexamethasone on loss of collagen from cartilage explants exposed to IL-1

Cartilage samples were maintained in serum-free medium (low-glucose DMEM, 10 mM HEPES) lacking insulin, transferrin, selenium, and in the presence of 1 ng/mL IL-1 throughout culture duration. Dexamethasone was added and maintained at a concentration of 10 nM. From reference , with permission

Figure 4. Effect of dexamethasone on the viability of chondrocytes within cartilage explants exposed to IL-1

Cartilage samples were maintained in serum-free medium (low-glucose DMEM, 10 mM HEPES) lacking insulin, transferrin, selenium and in the presence of 1 ng/mL IL-1 throughout culture duration. Dexamethasone was added and maintained at a concentration of 10 nM. From reference , with permission