Five-Year Goals and Objectives

The Bone and Joint Rehabilitation Research and Development Center of Excellence is committed to continuing to build upon its record of success. In the next five years, the Center is initiating research in five new specific areas focused on determining

1. how mechanical loading of the knee can be altered to slow progression of osteoarthritis (OA). The long-term goal of this project is to test a specific mechanism that would provide a mechanistic explanation of how obesity contributes to OA at the knee. In this clinical study we will determine if obesity is associated with either increased hyperextension or increased adduction moment. Our preliminary data suggest that these two parameters of gait kinematics contribute to the initiation and progress of knee OA. These parameters will also be related to cartilage thickness and the level of serum inflammatory markers of OA;

2. how obesity affects gait and loading at the knee and the progression of osteoarthritis. The goal of this project is to investigate the role of pathologic alterations in the mechanical loading of the knee in the initiation and progression of osteoarthritis. We hypothesize changes in the kinematics of gait initiate cartilage thinning and degeneration. We will focus on two disruptions to the soft-tissue structures of the knee that are well known to lead to OA, partial removal of the medial meniscus (meniscectomy) and rupture of the anterior cruciate ligament (ACL). In this clinical study we will quantify the knee kinematics of VA patients with either partial medial meniscectomies or ACL deficient knees and monitor them for changes in cartilage thickness. We will also determine to what extent ACL reconstruction is able to normalize gait to prevent OA progression and which aspects of the procedure might be optimized to enhance this effect;

3. evaluation of physical countermeasures designed to slow or prevent bone loss in elderly subjects and patients who have lower extremity disuse due to either stroke or spinal cord injury (SCI). The goal of this project is to evaluate to efficaciousness of physical interventions for the prevention of disuse bone loss associated with aging and lower extremity disuse associated with stroke and spinal cord injury. In the case of aging, elderly VA subjects will be assigned walking protocols of varying time, distances, and intensities. The number of steps taken and the forces applied to the foot will be recorded. In the lower extremity study, stroke and SCI patients will be exposed to partial body support treadmill walking with our Lokomat lower extremity robot system. In both cases the primary outcome variable will be bone density. We will also assay serum and urine levels of biomarkers of bone loss. The ability of specific loading protocols to preserve bone will be determined;

4. how novel mechanisms by which cellular transduction of mechanical forces contribute to bone loss and osteoarthritis. In both disuse bone loss and OA it is accepted that alterations of the physical environment of the cell lead to biological changes associated with disease initiation or progression. The goal of this project is to identify novel molecular mechanisms for converting extracellular physical signals into intracellular biochemical signals. In the case of bone loss we hypothesize that loading leads to changes in structural protein confirmation contributing to signal initiation. In the case of cartilage we propose that hydrostatic pressure due to loading alters membrane fluidity that modulates diffusion rates and kinetics of membrane bound G-proteins. Experimental approaches will include highly controlled tissue culture experiments and translation of findings with animal loading models. These experiments target development of the next generation of physical and pharmacologic interventions and are informed and focused by the translational environment of the Center; and

5. identifying optimal temporal loading patterns for prevention of bone loss. It is well established that physical activity contributes to the maintenance of bone and that disuse leads to bone loss. Preliminary experiments have demonstrated that the loading time history can dramatically affect the cellular response to loading. Specifically, the introduction of short rest periods has the potential to dramatically increase the osteogenic effect of loading. Our intention is to identify the temporal loading patterns that are most effective for the prevention of disuse bone loss. In this project we will take the first steps to translate this concept into clinical practice by determining which loading patterns are most osteogenic in vitro and in vivo.

These projects will be supported by shared core facilities that include a molecular biology and bone histomorphometry core, a biomotion lab, a biomechanics and materials testing facility, a bone imaging facility, and a computational modeling laboratory.