Abstract
Post-traumatic osteoarthritis can develop as a result of the initial mechanical impact causing the injury and also as a result of chronic changes in mechanical loading of the joint. Aberrant mechanical loading initiates excessive production of reactive oxygen species, oxidative damage, and stress that appears to damage mitochondria in the surviving chondrocytes. To probe the benefits of increasing superoxide removal with small molecular weight superoxide dismutase mimetics under severe loads, we applied both impact and overload injury scenarios to bovine osteochondral explants using characterized mechanical platforms with and without GC4403, MnTE-2-PyP, and MnTnBuOE-2-PyP. In impact scenarios, each of these mimetics provides some dose-dependent protection from cell death and loss of mitochondrial content while in repeated overloading scenarios only MnTnBuOE-2-PyP provided a clear benefit to chondrocytes. These results support the hypothesis that superoxide is generated in excess after impact injuries and suggest that superoxide production within the lipid compartment may be a critical mediator of responses to chronic overload. This is an important nuance distinguishing roles of superoxide, and thus superoxide dismutases, in mediating damage to cellular machinery in hyper-acute impact scenarios compared to chronic scenarios.
Highlights
The healthcare burden of post-traumatic osteoarthritis (PTOA) upon the United States is significant with a disproportionate number of young and active people suffering this disease as a result of trauma to joints in the lower extremities [1,2,3]
Only the highest dose of BuOE used, 1000 nM, produced a significant increase in mitochondrial content in the absence of mechanical load (n = 3, Figure 2C), though several other groups across the study statistically insignificantly trended higher than controls
The results presented here demonstrate that excess superoxide is likely contributing to cell death observed with impact injury but losses in mitochondrial function observed with chronic overloading or impact are not uniformly responsive to increasing superoxide removal capacity
Summary
The healthcare burden of post-traumatic osteoarthritis (PTOA) upon the United States is significant with a disproportionate number of young and active people suffering this disease as a result of trauma to joints in the lower extremities [1,2,3]. Even for less severe injuries like meniscal injuries, ligament tears, and dislocations, there are no currently available treatments to subvert development of disease later in life. Given this societal burden and lack of viable therapies prior to joint replacement, new approaches to preventing and treating PTOA are sorely needed. Many examinations of PTOA focused on improving surgical care have noted strong correlations between increased mechanical stresses and strains from injury to articular cartilage and subsequent PTOA development [11,12,13,14]
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