Evidence for acute inflammation in the pathogenesis of different mouse models of post-traumatic osteoarthritis
Date
2022
Authors
Timkovich, Ariel E., author
Santangelo, Kelly, advisor
Olver, Christine, committee member
Moreno, Julie, committee member
Goodrich, Laurie, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Post-traumatic osteoarthritis (PTOA) is a debilitating, degenerative condition affecting more than 5.6 million people in the United States. Following injury to the knee, a person is 4.2 times more likely to develop PTOA in that joint, compared to an uninjured joint. PTOA is characterized by clinical symptoms such as pain, swelling, and decreased range of motion of the knee or affected joint. As a leading cause of pain and disability, PTOA is a major contributor to a decreased quality of life. Notably, loss of mobility associated with PTOA can increase the risk of a multitude of other ailments including heart disease and diabetes. PTOA due to traumatic joint injury can result in damage to intra-articular structures, such as menisci, ligaments, cartilage, and subchondral bone. Despite current treatment options, many of these joint injuries progress to end-stage PTOA within 10 to 20 years. Rupture of the most commonly injured knee ligament, the anterior cruciate ligament (ACL), typically occurs in athletes and people who are physically active, with the majority of ACL tears occurring in patients who are less than 30 years old. The detrimental pathways driving PTOA remain loosely defined and little progress has been made in predicting, preventing, and treating the disease. The goal of this work was to further our understanding of PTOA mouse models through both development and characterization of models, as well as through the testing of therapeutics in pre-established PTOA mouse models. In the first part of this work (Chapter 2), we created and characterized a novel full and partial ACL rupture model. This work is the first published partial ACL rupture model to date and provides a novel platform to use as a preclinical model for testing of potential therapeutics and to further our understanding of PTOA following ACL rupture. Chapter 3 evaluates the therapeutic potential of a toll-like receptor 4 (TLR4) antagonist on a full depth PTOA model. We found that short term treatment with a systemic TLR4 antagonist significantly improved relevant gait parameters, and improved cartilage structural metrics and modified Mankin PTOA scores, implying improvement of clinical signs. Chapter 4 addresses the therapeutic potential of intra-articular bone marrow aspirate concentrate (BMAC), for treatment of PTOA in a well characterized meniscus degeneration model, compared to red blood cell (RBC) depleted BMAC or no injection controls. These results suggest that RBC-depleted BMAC improved treatment of PTOA in an animal model and may have translational therapeutic potential for humans suffering from similar disease processes. Finally, Chapter 5 sought to: (1) Identify transcriptional sex differences in knee joint tissue from naïve animals; and (2) Identify compensatory gene expression changes related to sex that are specific to animals receiving DMM surgery as compared to a naïve animal when taking into account surgery changes (i.e., sham surgery). The work described in this dissertation has improved our understanding of the mouse knee joint during PTOA progression and potential therapeutics and targets for clinical treatment of PTOA.
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Embargo Expires: 01/09/2025
Subject
osteoarthritis
preclinical models
post-traumatic osteoarthritis
animal models