PROJECT SUMMARY
Arthritis affects almost 60M adult Americans and is increasing in incidence, with osteoarthritis (OA) being the
most common form of arthritis. OA occurs due to degeneration of tissues comprising joints, and is associated
with pain. OA pain is a major contributor to the burden of chronic pain in society. About 80% of persons with OA
suffer movement limitations, and 25% cannot perform major activities of daily living. Current treatment options
are limited to steroid injections, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids and non-
pharmacological approaches (exercise, weight loss). Unfortunately, each of these therapeutic approaches are
problematic. Exercise, which helps weight management, is difficult for patients due to ongoing pain. NSAIDS can
cause gastrointestinal irritation and bleeding and increase risk of heart attack or stroke, and opioids are
associated with addiction and abuse (and can actually worsen chronic pain). Clearly, there is a critical need
to identify new therapeutic targets and/or treatments for individuals suffering from OA pain. Here, we
propose that a heretofore unrecognized neural pathway is a critical component of OA pain. This pathway involves
ARTN, its receptor GFRa3, and ‘pain’ channels on nerves (transient receptor potential [TRP] channels).
Activation of this pathway initiates and maintains OA pain. The central hypothesis (based on preliminary data in
multiple species [mouse, dog, cat, human]) is that ARTN, released from synovium of the OA joint in response to
injury, results in de novo increase in its receptor, GFRa3, in local and distant sensory nerves, producing local
and widespread pain and hypersensitivity via Proto-oncogene tyrosine-protein kinase receptor (RET)-mediated
upregulation of multiple downstream TRP receptors. In this proposal, we will use multiple OA models and
clinically relevant outcome measures, and leverage our unique access to dogs with naturally occurring OA, to
achieve the following aims: Aim 1: To test the hypothesis that ARTN expression is increased in OA and is
responsible for pain. Aim 2: To test the hypothesis that ARTN/GFRa3 signaling is responsible for behaviorally
manifested OA pain both in early and late stage disease. Aim 3: To test the hypothesis that RET-dependent
ARTN/GFRa3 signaling results in changes in multiple TRP channel expression and activation. Aim 4: To
test/validate involvement of the above-described key molecules in a naturally occurring large animal model of
OA (dog). Overall, this will be the first work investigating the role and mechanisms of ARTN/GFRa3/TRP channel
in OA pain and sensitivity. Based on solid, clinically relevant preliminary data, and leveraging PI expertise from
two different and complementary disciplines, successful completion of this proposed work has the potential to
identify clinically relevant neural mechanisms leading to the development of novel, effective therapeutics for the
treatment of OA-pain in humans.
