Graduate Student Michael David will be defending his dissertation on Wednesday, February 27th @ 9:30 am at the Delaware Biotechnology Institute (15 Innovation Way) Room 102
Local, Intra-Articular Delivery of Zoledronic Acid as a Disease-Modifying Therapeutic for Post-Traumatic Osteoarthritis
When: Wednesday, February 27th @ 9:30 am
Where: DBI Room 102
Committee Chair: Dr. Christopher Price
Committee: Dr. Dawn Elliott, Dr. Randall Duncan, Dr. Jason Gleghorn
Post-traumatic osteoarthritis (PTOA) is the result of a traumatic joint injury, e.g., meniscus or ligament tears in the knee joint. Approximately 20-50% of patients experience cartilage degeneration, altered subchondral bone remodeling, inflammation, and pain within 10-15 years post-injury in the afflicted joint. Currently, PTOA is incurable and existing treatments can only delay costly total joint replacements. Thus, a significant unmet clinical need exists for disease-modifying therapies that can slow or stop PTOA progression. This dissertation highlights a potential biologically-driven solution using a bisphosphonate.
Bisphosphonates (BPs) have recently received significant attention as potential disease-modifying therapeutics for PTOA. BPs are an FDA-approved class of drugs historically used to treat bone-related diseases by preventing bone resorption and remodeling. Given this property and the general belief that subchondral bone remodeling may influence cartilage degeneration following an injury to the knee joint, BPs have been explored in preclinical models of PTOA. Specifically, the newest and most potent BP, zoledronic acid (ZA), has shown promising results when administered systemically at high doses in numerous animal models of PTOA. Unfortunately, high-dose and systemic administration of ZA is associated with adverse side effects, hampering its clinical translatability and warranting the development of alternative delivery strategies. Thus, most of this dissertation was dedicated to evaluating an alternative strategy of local, intra-articular delivery of ZA for treating cartilage degeneration and modifying the evolution of non-cartilaginous tissue changes in a mouse model of PTOA. Despite the preclinical evidence supporting the use of intra-articular delivered ZA for PTOA, ZA’s direct effects and mechanisms of action on cartilage cells (chondrocytes) were largely unknown, compelling the final in vitro work of this dissertation.
Through this dissertation, we reveal that injury-induced cartilage degeneration in the mouse knee is associated with an immediate loss of resident chondrocytes that appears to precipitate and ultimately propagate the focal development of cartilage erosions. We further demonstrate the ability of local, intra-articular delivered ZA into the injured joint to suppress cartilage erosions by spatiotemporally modulating the underlying chondrocyte biology and cartilage composition. We also show intra-articular ZA’s ability to modify the evolution of non-cartilaginous tissue changes associated with injury-induced PTOA while exerting minimal influence on bone compartments distant from treated joints. Lastly, our in vitro findings demonstrate that ZA exerts direct, concentration- and exposure-dependent pleiotropic effects on chondrocytes.
Collectively, this dissertation provides a fundamental understanding of changes to the whole-joint following a traumatic joint injury and the efficacy of locally delivered ZA for PTOA prevention in a preclinical mouse model. Additionally, this work provides the foundation for future studies to leverage local delivery of ZA most optimally. Most importantly, this work has the potential to help accelerate the translation of a novel, safe, and inexpensive strategy for PTOA disease-modification based upon the local, intra-articular delivery of ZA to acutely injured joints.