Discovering the Mechanisms Linking Gait to Osteoarthritis Onset and Progression - PROJECT SUMMARY Developing innovative solutions to prevent disease onset in individuals at high-risk for knee osteoarthritis (KOA) is paramount to advancing overall societal health and promoting the economic stability of our healthcare system. Aberrant limb-level loading during walking is hypothesized to be a determinant of disease onset in young individuals at high-risk of KOA following knee injury, thus positioning precision gait rehabilitation as a critical future intervention to reestablish limb-loading strategies to mitigate KOA onset. However, the current evidence linking aberrant gait biomechanics with KOA development is primarily observational and lacks the fundamental scientific rigor of an established mechanistic pathway to explain how limb-level loading alters mechanical, biophysical, and biological properties of tibiofemoral articular cartilage. Identifying the underlying mechanistic pathway linking limb-level loading to articular cartilage changes is the single most important scientific knowledge gap that needs to be overcome to advance precision gait retraining as a strategy for KOA prevention. Our overarching hypothesis is that a sustained compressive limb-level loading biomechanical gait phenotype, which is found in individuals at high risk for KOA following knee injury, leads to aberrant sustained tibiofemoral articular contact forces (i.e., mechanical), causing greater cartilage strain (i.e., biophysical) and more deleterious changes to cartilage composition and joint tissue metabolism (i.e., biological), thereby contributing to KOA development. We hypothesize that directly modifying the sustained limb-level loading profile with dynamic limb-level loading will reverse these deleterious mechanical, biophysical, and biological cartilage changes. The proposed R01 will overcome this scientific gap and test our overarching hypothesis: i) in vivo using real-time gait biofeedback to precisely adjust limb-level loading in participants with anterior cruciate ligament reconstruction (ACLR) and determine resultant acute biomechanical and biophysical tissue changes and the cumulative biological cartilage changes caused by sustained and dynamic limb-level loading conditions; and ii) ex vivo using human articular cartilage explants to directly apply phenotypic loading profiles to the tissue, establishing a critical cause-and- effect understanding of sustained and dynamic loading on tissue mechanics, biology, and histology. Completion of our three specific aims will: 1) determine the acute in vivo mechanistic link between sustained and dynamic limb-level loading on mechanical and biophysical tibiofemoral articular cartilage outcomes; 2) determine the cumulative in vivo mechanistic link between sustained and dynamic limb-level loading and biological tibiofemoral articular cartilage outcomes; and 3) use an ex vivo experiment in human cadaveric tissue to establish the cause- and-effect relation between phenotypic (sustained vs. dynamic) loading and biological, biophysical, and histological changes in articular cartilage explants. Our R01 is innovative, as it is the first to study a mechanistic pathway defining the link between sustained limb-level loading and outcomes associated with KOA development and significant as the knowledge gained will directly inform development of future precision gait rehabilitation.
