PROJECT SUMMARY
Anterior cruciate ligament (ACL) rupture is a common injury on young active subjects that have long term
debilitating consequence. Meta analysis studies have demonstrated that 50% of the subjects after ACL rupture
generate posttraumatic osteoarthritis (PTOA) 10 to 20 years after injury regardless of their clinical treatment.
Perpetuation of the inflammatory response to injury is hypothesized as an important factor in the process
of joint degeneration, thus representing an attractive target for therapy. In general, the inflammation observed
in PTOA is chronic, low-grade, mediated primarily by the innate immune system. Although several
mechanisms have been identified that can activate the inflammatory response in vitro, there is little
known on how the inflammatory response occurs in vivo, since we lack the technology to track
inflammation in vivo. Current methods to assess joint inflammation in vivo are not tissue-specific like the
analysis of inflammatory factors, or lack the biological specificity such as imaging. Molecular imaging
represents a natural approach to address the pathogenesis of PTOA, since it can image inflammation
processes at the molecular level with complete joint coverage. Our research aims to develop a new imaging
technology to measure the low-grade inflammation in PTOA in vivo using mimetic peptides that specifically
target the interaction of hyaluronic acid with the cell surface receptor CD44, which play important roles in
inflammatory signaling. The proposed mimetic peptides have shown anti inflammatory effect in cancer and
rheumatoid arthritis, but their value in OA has not been explored. The selected molecular targets are
preserved cross-species, so our research has potential for clinical translation. To capture different pathways
on the same subject we propose to use a multimodal imaging approach combining magnetic resonance
imaging (MRI) and near infrared (NIR) imaging. We will conduct experiments to validate the contrast
agents in vitro. We will assess in vivo the contrast agent pharmacokinetics at early and late stage of disease,
and control-validate. Finally, we will test the contrast agents in a longitudinal study. The results of this
proposal will provide a platform to elucidate the pathophysiology of PTOA, help identifying new
therapeutic targets, and track therapy response.