UC Davis

Osteoarthritis (OA) is a degenerative disease of the joints which is recently understood to develop from inflammatory pathology. Injury to a joint is major risk factor for developing osteoarthritis known as post-traumatic osteoarthritis (PTOA). Trauma to a joint initiates inflammation and immune infiltration by the release of damage-associated molecular patterns, and alarmins. This event may only occur once in the lifetime of a joint. However, this event makes the joint more likely to develop OA in the following years and decades. To date, there are no disease modifying drugs for PTOA or OA, and surgical repair of joint structure and tissues is inadequate to reverse this inflammatory joint environment. This highlights need to further our understanding of inflammation in the joint and how we might potentially address it. PTOA models provide a valuable initial bolus of inflammation to study, which is known to then develop into osteoarthritis.

The work presented here is an investigation of this early period of inflammation after joint injury and subsequent PTOA using animal models. The first chapter details novel protocols for wholistically sequencing the murine knee at the single cell level. This methodology allows the study of the joint as an organ and captures the cross-talk between immune cells and stromal cells. The second chapter characterizes the first hours after injury in a small animal model and defines the Acute Injury Response (AIR) in murine knees. Understanding the AIR provided rich targets for further study into the subsequent development of OA. Chapter three reviews large animal models of PTOA, specifically the field of ovine PTOA models to inform investigators in future studies. Lastly – the forth chapter – assesses the safety and dosage of a potential anti-inflammatory therapy in horses, revealing the safety, tolerability and pharmacokinetics of a time release injection in horse knees.

Together this work expands our understanding of early inflammatory processed in injured knees leveraging multiple animal models and ultimately leading towards a potential therapeutic.