There is a considerable gap in our understanding of the early onset of osteoarthritis (OA) following traumatic knee injury and how degenerative metabolic, inflammatory and biomechanical processes can influence the initial stages of cartilage degradation and diminished cartilage health. The investigator's long-term goal is to develop multi-modal treatments to slow the progression to OA immediately following traumatic joint injury. We hypothesize that traumatic knee injury may initiate a multifaceted degenerative process, which consists of metabolic, inflammatory and biomechanical influences, that culminates in the development of knee OA. It is unknown which factors have the greatest influence on early OA onset, which factors to target with treatments, and how novel treatments will affect the multiple factors associated with early OA development. The objective of this R03 application is to develop a comprehensive evaluation strategy for determining early changes in joint homeostasis that underlie OA development following anterior cruciate ligament reconstruction (ACL-R). We will leverage an ongoing project that is currently recruiting ACL-R patients to achieve our objective. The proposed comprehensive evaluation strategy is fundamental for developing future studies that evaluate therapeutic targets and interventions to prevent early OA progression. It is critical to establish the infrastructure needed to systematically collect a comprehensive group of outcome measures (joint tissue metabolism, joint inflammation, biomechanics, and magnetic resonance imaging [T1rho MRI] of cartilage health). Simultaneous collection of the aforementioned outcome measures is necessary to improve our understanding of the overall multifaceted nature of early OA development. The proposal encompasses two specific aims to: 1) determine exploratory associations between a comprehensive group of outcome measures (joint metabolism, joint inflammation, biomechanics and T1rho MRI of cartilage health) in the injured and uninjured limbs of 20 ACL patients at initial presentation (pre-surgical) and at 12-months post ACL-R, and 2) determine effect sizes between ACL injured and uninjured limbs at initial presentation following injury and 12 months following ACL-R as well as the change over time for each limb in the outcome measures listed in Aim 1. This approach is innovative because: 1) it encompasses a novel comprehensive evaluation strategy, which has not been used by others, to assess the most influential aspects of early progression to OA following ACL injury, and 2) uses T1rho MRI as an innovative marker of cartilage health, which allows us to apply this evaluation strategy in a rapidly progressive ACL-R model to evaluate the very early changes in the development of OA. Acquiring these outcomes within the first 12 months following ACL injury is important, as this is the earliest that posttraumatic changes can be currently measured. The proposed R03 is significant because it will develop a comprehensive evaluation strategy that will be used to 1) discern associations between potential risk factors of early knee OA onset, and 2) determine the efficacy of future interventions to prevent OA onset.
The proposed research is relevant to public health because it is a fundamental step in understanding the early, multifaceted development of posttraumatic knee osteoarthritis, a disease that affects millions of Americans each year. Therefore, this proposed research is relevant to the NIH mission pertaining to the development of successful, cost-effective interventions that reduce the risk of knee osteoarthritis development and the economic burden of the disease by producing high returns on public investment in medical research.
| Davis, Hope C; Spang, Jeffery T; Loeser, Richard F et al. (2018) Time between anterior cruciate ligament injury and reconstruction and cartilage metabolism six-months following reconstruction. Knee 25:296-305 |
| Pfeiffer, Steven; Harkey, Matthew S; Stanley, Laura E et al. (2018) Associations Between Slower Walking Speed and T1? Magnetic Resonance Imaging of Femoral Cartilage Following Anterior Cruciate Ligament Reconstruction. Arthritis Care Res (Hoboken) 70:1132-1140 |
| Pietrosimone, Brian; Loeser, Richard F; Blackburn, J Troy et al. (2017) Biochemical markers of cartilage metabolism are associated with walking biomechanics 6-months following anterior cruciate ligament reconstruction. J Orthop Res 35:2288-2297 |
