Project Summary
A 2010 public awareness campaign entitled “Fight Arthritis Pain” promoted moving is the best medicine!
While clinical studies overwhelmingly confirm exercise is an effective osteoarthritis (OA) treatment, patients often
find this advice counterintuitive - “The solution for a painful joint is to use it more?” Part of this confusion is driven
by chondrocentric definitions of OA, which imply that more cartilage damage will lead to more pain. However,
OA is a `disease of the joint as an organ' with changes occurring throughout the joint. Moreover, factors that
affect OA pain and disability occur both within and beyond the articular joint, including changes in joint structure,
inflammation, and neuroplasticity. Understanding how these complex factors contribute to the patients' primary
concerns - pain and disability - can help identify critical targets for OA therapy.
Preclinical OA models should be a powerful tool to help researchers identify physiologic links between OA
pathogenesis and symptomology, offering an opportunity to investigate facets of OA that cannot be easily
explored in humans. Toward this goal, this proposal will use novel rodent gait analyses and measures of hind
limb sensitivity to investigate how changes in joint structure, intra-articular inflammation, and dorsal root ganglia
neuroplasticity relate to the development of OA-related pain and disability in rat models of post-traumatic knee
OA. First, 3D measures of bony structures will be acquired in our models using a nanoCT, and 3D changes in
cartilage and synovium will be assessed using selective plane illumination microscopy (SPIM) on optically-
cleared knees (Aim 1). This aim will allow us to investigate relationships between complex 3D joint structures
and OA-related pain and disability. Second, the missing link between OA pathogenesis and OA pain is often
assumed to be inflammation, which can temporally cycle without major shifts in joint structure. In this proposal,
intra-articular inflammation will be directly examined in our models; moreover, the distribution and quantity of
macrophages will be examined using SPIM on optically cleared knees (Aim 2). Third, chronic exposure to low
grade inflammation can lower the threshold of dorsal root ganglia (DRG) neurons. In this proposal, patch clamp
recordings will be used to investigate DRG sensitization subsequent to simulated joint injuries (Aim 3).
Additionally, all studies will be collected in the context of OA-related pain and disability, using mechanical
hypersensitivity testing and gait analysis to quantify OA-related symptoms in the rat. Finally, a well-established
and effective OA therapy - moderate exercise - will be evaluated in each aim to discern how exercise modifies
the physiology of the OA-affected knee and leads to improvement in OA-related symptoms. Overall, this
approach will use innovative, quantitative methods to simultaneously study joint structure, inflammation, and
neuroplasticity in a manner that is not possible in humans, allowing us to assess how these mechanisms
contribute to the continuum of OA pain and disability.
