2021 conference paper
Artemin and its cognate receptor, GFRΑ3, Play a function role in osteoarthritis pain
Osteoarthritis and Cartilage, 29, S372.
www.oarsijournal.com (publisher PDF)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(OpenAlex)
Source: ORCID
Added: June 10, 2022
Purpose: Osteoarthritis associated pain (OA-pain) is a significant global problem. OA-pain limits limb use and mobility, and is associated with widespread sensitivity. Therapeutic options are limited, and the ones that are available are often associated with side or adverse effects. The lack of therapeutic options is partly due to a lack of understanding of clinically relevant underlying neural mechanisms of OA-pain. In previous work in naturally occurring OA-pain in dogs, we identified potential signaling molecules (artemin/GFRα3) that were upregulated. Artemin/GFRα3 signaling is known to play a role in various pain states (mainly models of pain), including a recently reported inflammatory bone pain model. Artemin/GFRα3 is thought to potentiate pain via the upregulation and/or sensitization of various transient receptor potential (TRP) receptors. To date, no work has been performed to evaluate the role of artemin/GFRα3 in OA-pain. The purpose of this study was to explore the functional role of artemin/GFRα3 signaling in OA-pain. Methods: To examine the functional role of artemin/GFRα3 signaling in OA-pain, we used a mouse model of stifle (knee) OA based on the intra-articular injection of mono-iodoacetate (MIA). Following induction of OA using MIA, we assessed sensitivity to heat, mechanical and cold pain, and evaluated limb use, weekly to 28 days or longer. At the same timepoints, heat, mechanical, and cold sensitivity was assessed in TRPV1 KO mice with MIA arthritis to define the role of TRPV1 in MIA-induced sensitivity. Using artemin injections into the footpad, we evaluated the acute changes in heat, mechanical, and cold sensitivity. In male and female mice with MIA-induced OA, we assessed the anti-hypersensitivity effects of an anti-artemin antibody at day 28, and assessed the effects of an anti-artemin antibody on limb use measured while walking and standing (Catwalk assay, and pronograde incapacitance meter) at day 40. Results: We found the mono-iodoacetate (MIA)-induced OA model in mice is associated with significantly decreased limb use (both kinetic and static measures) and hypersensitivity to heat, mechanical, and cold. Mechanical and cold sensitivity in TRPV1 KO mice with MIA-induced OA were not significantly different from wild type mice with MIA-induced OA; there was some mitigation of heat hypersensitivity in the TRPV1 KO animals. Using immunohistochemistry, we found that GFRα3 expression in sensory neurons of the dorsal root ganglions serving the stifle joints was increased from ∼20% of neurons to ∼40% in mice with MIA OA. In naïve mice, exogenous artemin induced heat, cold and mechanical hypersensitivity for between 2 and 6 hours following injection. An anti-artemin monoclonal antibody administered intraperitoneal on day 28 following MIA-induction of OA reversed mechanical and cold hypersensitivity for between 2 and 4 hours following injection, and between 2 and 6 hours for heat hypersensitivity. Approximately 40 days following MIA-induction of OA, an anti-artemin antibody restored limb use to normal (both kinetic and static) in mice with MIA-induced OA pain for ∼48 hours. Conclusions: Overall, we present the first evidence of a potential functional role of artemin/GFRα3 in chronic OA-pain. However, there is much to understand about the potential role of artemin, including the mechanisms leading to artemin release and which cells types in the joints are responsible for artemin release; whether artemin is involved in the induction and/or maintenance of OA-pain; and whether artemin acts through only GFRα3, or other receptors (such as NCAM) are involved. Also, the degree to which artemin may drive the ultimate experience of OA pain needs to be fully elucidated. Although we have found that artemin’s cognate receptor, GFRα3, was upregulated in MIA induced OA-pain, paralleling what we found in the naturally occurring OA model in the dog, work needs to be done to determine the contribution of GFRα3 upregulation and/or activation in OA pain, and further, the downstream targets and signaling mechanisms need to be unraveled.