A single administration of dexamethasone may protect tibial plateau cartilage in a mechanically stable surgical model of post traumatic osteoarthritis

Abstract

Purpose: An acute inflammatory phase follows an injury to the knee joint and initiates a cascade of biochemical events that can contribute to degeneration of the cartilage. Cartilage degeneration after injury is central in the development of posttraumatic osteoarthritis (PTOA) – a debilitating disease that is increasingly affecting active younger individuals. It is currently believed that inflammation following intra-articular bleeding from joint injuries could be a cause in the development of PTOA. To study the effects of inflammation alone within the joint, an injury model was developed in which tissue structures responsible for joint function and stability were not directly impacted. Preliminary evidence in this rabbit model of intra-articular bone injury, intended to simulate posttraumatic hemarthrosis, has shown what appears to be an acute inflammatory phase that resolves after surgery and yet still results in the development of significant PTOA. Therefore, we hypothesize that if insult to the joint increases the expression level of acute inflammatory mediators that expose the cartilage to injury then an intervention that inhibits acute inflammation (dexamethasone) will have positive outcomes on cartilage health within this rabbit bone injury model. Dexamethasone (dex) is a glucocorticoid with potent anti-inflammatory properties that has been widely adopted for clinical use (e.g. in the treatment of rheumatoid arthritis, asthma, and various cancers). Methods: Skeletally mature adult female rabbits aged 52 weeks (n = 18) were used in this study. Six animals were not subjected to any interventions and served as un-operated controls. The remaining 12 were all subjected to a femoral notch drill surgery following the guidelines of our institutional animal care facility. Of this group, six rabbits were treated with one intra-articular injection of Dex (0.5 mg/kg) at the time of surgery. As surgical controls, the remaining 6 animals were subjected to drill surgery, but did not receive any dexamethasone treatment. Animals were sacrificed at 9 weeks post surgery. Histological assessment was completed by two blinded observers using a modified Mankin protocol. qPCR was used to analyze the mRNA levels for select anabolic and catabolic molecules, and values were normalized to 18S mRNA. Kruskal-Wallis with Dunn’s multiple comparisons test were used to investigate treatment group differences (significance accepted at p ≤ 0.05). Results: Histological evaluations (Figure 1A) revealed that at 9 weeks post surgery the cartilage on the tibial plateaus of the drill animals was significantly more damaged than that of the un-operated controls and the animals that received the dex treatment after injury. There were no significant differences between the tibial plateau cartilage of the normal and drill + dex treatment groups, suggesting a positive role for dexamethasone. Furthermore, the mRNA analysis (Figure 1B) revealed that even a single dose of dexamethasone at the time of surgery, was sufficient to attenuate the expression of degradative proteinase matrix metalloproteinase 3 (MMP-3), proteoglycans such as versican and biglycan as well as anabolic marker collagen type II (Col-II) in tibial plateau cartilage. Conclusions: Even in the absence of severe biomechanical changes, the cartilage of the tibial plateau is subject to degeneration in this model. This strongly suggests that initial biological changes are sufficient to drive many of the changes observed within the joint. The results of this study suggest that Dexamethasone treatment given at the time of drill surgery had a positive impact in reducing the degradation of the cartilage covering the tibial plateau. Interestingly, treatment with this steroid attenuated the mRNA levels for both anabolic and catabolic molecules.