@article{shih_kingsley_newman_hoque_gupta_lascelles_varghese_2023, title={Multi-Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing}, volume={11}, ISSN={["2198-3844"]}, url={http://dx.doi.org/10.1002/advs.202303567}, DOI={10.1002/advs.202303567}, abstractNote={Abstract}, journal={ADVANCED SCIENCE}, author={Shih, Yu-Ru V. and Kingsley, David and Newman, Hunter and Hoque, Jiaul and Gupta, Ankita and Lascelles, B. Duncan X. and Varghese, Shyni}, year={2023}, month={Nov} }
 @article{minnema_gupta_mishra_lascelles_2022, title={Investigating the Role of Artemin and Its Cognate Receptor, GFR alpha 3, in Osteoarthritis Pain}, volume={16}, ISSN={["1662-453X"]}, url={https://europepmc.org/articles/PMC8829392}, DOI={10.3389/fnins.2022.738976}, abstractNote={Osteoarthritis (OA) 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 available options are often associated with 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. Here, we use multiple approaches, including cellular, mouse genetic, immunological suppression in a mouse model of OA, and clinically relevant measures of sensitivity and limb use to explore the functional role of artemin/GFRα3 signaling in OA-pain. We found the monoiodoacetate (MIA)-induced OA-pain in mice is associated with decreased limb use and hypersensitivity. Exogenous artemin induces mechanical, heat, and cold hypersensitivity, and systemic intraperitoneal anti-artemin monoclonal antibody administration reverses this hypersensitivity and restores limb use in mice with MIA-induced OA-pain. An artemin receptor GFRα3 expression is increased in sensory neurons in the MIA model. Our results provide a molecular basis of arthritis pain linked with artemin/GFRα3 signaling and indicate that further work is warranted to investigate the neuronal plasticity and the pathways that drive pain in OA.}, journal={FRONTIERS IN NEUROSCIENCE}, author={Minnema, Laura and Gupta, Ankita and Mishra, Santosh K. and Lascelles, B. Duncan X.}, year={2022}, month={Jan} }
 @inproceedings{lascelles_minnema_gupta_mishra_2021, title={Artemin and its cognate receptor, GFRΑ3, Play a function role in osteoarthritis pain}, volume={29}, url={http://dx.doi.org/10.1016/j.joca.2021.02.483}, DOI={10.1016/j.joca.2021.02.483}, abstractNote={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.}, booktitle={Osteoarthritis and Cartilage}, publisher={Elsevier BV}, author={Lascelles, D. and Minnema, L. and Gupta, A. and Mishra, S.}, year={2021}, month={Apr}, pages={S372} }
 @article{gupta_chiavaccini_minnema_chiu_knazovicky_hash_mishra_lascelles_2021, title={Serum artemin is not correlated with sensitivity within dogs with naturally occurring osteoarthritis pain}, volume={11}, ISSN={["2045-2322"]}, url={https://europepmc.org/articles/PMC7988108}, DOI={10.1038/s41598-021-85976-y}, abstractNote={Abstract}, number={1}, journal={SCIENTIFIC REPORTS}, author={Gupta, Ankita and Chiavaccini, Ludovica and Minnema, Laura M. and Chiu, King Wa and Knazovicky, David and Hash, Jonathan A. and Mishra, Santosh K. and Lascelles, B. Duncan X.}, year={2021}, month={Mar} }
 @article{altered salt taste response and increased tongue epithelium scnna1 expression in adult engrailed-2 null mice_2018, url={http://dx.doi.org/10.1016/j.physbeh.2018.06.030}, DOI={10.1016/j.physbeh.2018.06.030}, abstractNote={Sensory impairments are critical for diagnosing and characterizing neurodevelopmental disorders. Taste is a sensory modality often not well characterized. Engrailed-2 (En2) is a transcription factor critical for neural development, and mice lacking En2 (En2−/−) display signs of impaired social interaction, cognitive processes (e.g., learning and memory, conditioned fear), and neurodevelopmental alterations. As such, En2−/− mice display the behavioral deficits and neural impairments characteristic of the core symptoms associated with autism spectrum disorder (ASD). The objective of this study was to characterize the taste function in En2−/− compared with En2+/+ in adult male mice. Measuring taste responsiveness by an automated gustometer, En2 null mice had decreased lick responses for 1.6 M fructose, whereas they demonstrated an increased taste responsivity (i.e., relative to water) at 0.3 M sodium chloride and 1 M monosodium glutamate. In a separate cohort of mice, En2−/− mice had an increased preference for sodium chloride over a range of concentrations (0.032–0.3 M) compared with En2+/+ mice. Regional gene expression of the tongue epithelium demonstrated an increase in Scnn1a, T2R140, T1R3, and Trpm5 and a decrease in Pkd1l3 in En2 null mice. Taken together, such data indicate that deficits in En2 can produce sensory impairments that can have a measurable impact on taste, particularly salt taste.}, journal={Physiology & Behavior}, year={2018}, month={Oct} }