The rat homolog to FX201, a gene therapy in development for the treatment of osteoarthritis, demonstrates dose-dependent decreases in the severity of cartilage and bone lesions following anterior cruciate ligament transection

Abstract

using a two-way ANOVA with significance evaluated at p &lt 0.05 for both bulk tissue and depth-dependent results. Results: Bulk tissue analysis revealed that individually, impact and sliding caused increased chondrocyte death and damage for all assessments, with impact having the greater effect, however the combination further increased cell damage and death (Figure 1A-C). For cell death and apoptosis, the effects of impact and sliding were additive, while for MT depolarization the effect was more than additive (Figure 1C) (p ¼ 0.016 for interaction via two-way ANOVA). Examining the spatial patterns of chondrocyte damage and death (Figure 2A-C) revealed that all treatments resulted in cell damage and death that was highest near the articular surface and decreased with depth from the surface. In controls cell death, apoptosis, and MT depolarization were unaffected deeper in the tissue. Sliding alone resulted in levels of cell death, apoptosis, and MT depolarization that were not different from controls deeper into the tissue (p &gt 0.05). Impact alone increased cell death, and MT depolarization in the deeper regions of the cartilage compared to controls (p &lt 0.05). The combination of impact and sliding was nominally higher than either impact or sliding alone, but the interaction was only statistically higher for MT depolarization (Figure 2C). This combination resulted in dramatically higher MT depolarization deeper in the tissue compared to the impact only group (~60% vs~30%, p ¼ 0.005). Conclusions: The goal of this study was to assess the combined effects of two types of loading experienced in joints after trauma. The data show that both impact injury and sliding affect chondrocyte damage. Damage was primarily concentrated at the articular surface, which indicates the surface acts as a protective layer to limit damage propagation deeper into the tissue. Assessments of cell death and apoptosis show additive effects of the combination treatment. However, this combination causes synergistic damage in the assessment of MT depolarization, particularly deeper in the tissue. This population of cells with MT depolarization represents a possible mechanism by which damage propagates to other areas of the tissue and joint. As such this cell population represents a potential target for therapy.