Date of Award
Doctor of Philosophy (PhD)
Post-traumatic osteoarthritis (PTOA) is a painful and debilitating disease of the synovial joint, characterized by degenerative changes to various joint tissues following traumatic joint injury. While several risk factors have been identified in the symptomatic progression of PTOA following injury, inflammation and NF-κB mediated changes are believed to significantly contribute to symptomatic joint dysfunction and pain. However, the temporal presentation of these pro-inflammatory signals following clinically relevant injury and their relationship to the development of symptomatic disease have not been thoroughly investigated. Therefore, there exists a critical need to better understand how these early inflammatory events following injury may contribute to the symptomatic progression of PTOA.
In the first aim of this dissertation, the temporal relationship between NF-κB activation and the development of pain-sensitivity related behaviors following joint injury was evaluated in a non-invasive murine model of PTOA. Early activation of NF-κB following traumatic knee joint injury was associated with several clinically relevant changes in animal behavior including the acute presentation of allodynia, hyperalgesia, and transient alterations to weight bearing and ambulation/gait. Persistent unilateral allodynia was observed up to 4 months following injury. Furthermore, early NF-κB activation following injury was correlated with the severity of chronic allodynia and erosive changes to articular cartilage. Data from this aim was used to define an early therapeutic treatment window to test the efficacy of a locally delivered NF-κB inhibitor, PHA-408, following joint injury.
Given the involvement of the NF-κB pathway in inflammation and in the development of symptomatic PTOA, it was hypothesized that acute local pharmacologic NF-κB inhibition might slow the progression of symptomatic PTOA following joint injury. Findings in this aim highlighted the early chondroprotective effects of local PHA-408 following mechanical joint injury. Modest improvements in pain-sensitivity related outcomes with repeated drug treatment were also observed. Nevertheless, local delivery of PHA-408 failed to modify long-term degenerative changes to articular cartilage. Engineered drug depots were also developed for the sustained release of PHA-408. While these microparticle based depots showed the potential for sustained drug release and inhibition of NF-κB in vitro, their use did not improve measured outcomes following joint injury.
While the painful symptoms and debilitating impact of chronic conditions, such as PTOA, may be apparent to the patients who suffer from the disease, many aspects of sensory excitability which may contribute to pain, particularly in intact tissue, remain unclear. Work in the final aim of this dissertation described the development of an ex vivo imaging approach to functionally evaluate sensory neuron excitability within intact dorsal root ganglion tissues. This method was capable of simultaneously assessing functional signaling dynamics in hundreds of neurons with single-cell resolution and was further able to evaluate alterations to neural signaling following pharmacologic modulation and injury.
Overall, this dissertation serves to improve our understanding of the symptomatic progression of PTOA following traumatic joint injury and highlights many of the challenges of intra-articular drug delivery in the disease-modifying treatment of PTOA. Furthermore, the novel imaging methods developed within this dissertation may help to elucidate the structural and functional changes to musculoskeletal and peripheral nervous system tissues following injury, respectively.
Lori A. Setton
Farshid Guilak, Matthew J. Silva, Spencer P. Lake, Gabriel Mbalaviele,