By comparing osteoarthritis pain pathways known to be active in dogs and humans to those in cats with degenerative joint disease (DJD), researchers found that elevation of a particular molecule, artemin, could serve as a marker of disease (and possibly pain) as well as a potential therapeutic target. The findings offer the most comprehensive evidence to date that naturally occurring osteoarthritis (OA) in cats mirrors important biological features of human disease.

DJD, the main form of which is osteoarthritis, affects humans and all animals, including cats. However, the mechanisms underlying DJD-associated pain in cats are poorly understood.

In humans and dogs, transient receptor potential (TRP) ion channels – cellular sensors for a wide spectrum of physical and chemical stimuli that are found in the spinal cord’s dorsal root ganglia (DRG) – are activated to express osteoarthritis pain. One mechanism by which TRP ion channels can be activated is by a molecule called artemin. When artemin binds to its receptor, GFRA-3, it sends a signal to activate TRP channels, leading to a series of events which register the pain.

“We know that Artemin/GFRA-3 induced changes to TRP channels play a role in osteoarthritis pain in humans and dogs, but didn’t know whether cats shared this biological pathway,” says Santosh Mishra, associate professor of neurobiology at North Carolina State University and co-corresponding author of the study.

“With relatively limited options for managing chronic pain in cats, if we can understand more about how the sensation of pain is being generated in cats themselves, then we will be a step closer to developing therapies that are effective in cats,” adds Duncan Lascelles, professor of translational pain research at NC State. Lascelles is a co-corresponding author of the study.

The research team, comprised of experts in integrated molecular neuroscience, clinical pain phenotyping and translational methodology, designed an interdisciplinary study that yielded a robust data set.

First, they did detailed pain and DJD status assessments on more than 70 cats so that they could accurately compare samples from healthy and DJD cats. Then they looked at blood serum and DRG tissue samples from both healthy cats and cats with DJD.

The researchers confirmed that the TRP channels commonly associated with osteoarthritis pain in humans and dogs were expressed and functional in healthy cat DRG neurons. Then they compared expression of the TRP channels and GFRA-3 in healthy cats to those with DJD. Finally, they compared artemin concentrations in blood samples from healthy cats and cats with DJD.

They found that the TRP pathways associated with pain were active in healthy and DJD cats, and that increased artemin blood concentrations were correlated with radiographic or X-ray confirmation of DJD, but not necessarily with pain.

“These results are interesting for a couple of reasons,” Mishra says. “First, we now know that the biological pathways are similar, but the differences are also important.

“We saw that artemin levels were increased in cats with radiographic evidence of the disease, but that artemin levels didn’t correlate to veterinarian-assessed pain. However, knowing how difficult it is to measure pain in cats, in future work we will utilize technology to more objectively measure pain.”

The researchers also point to the elevated artemin in blood serum as a biological marker of osteoarthritis in cats as well as a potential therapeutic target.

“If veterinarians could do a blood test for increased artemin to diagnose DJD instead of X-rays it would save time and stress for cats,” Mishra says. “And perhaps targeting artemin expression could be therapy for either pain or disease progression. Now that we know the pathway is conserved, we can dig deeper into the mechanisms to find therapies.”

“Because cats exhibit naturally occurring DJD/OA similar to people, this work provides a valuable window into real biological processes and pain mechanisms which will ultimately improve clinical care for cats,” says Lascelles. “The findings may also help refine translational models and inspire cross‑species therapeutic advances.”

The study appears in Frontiers in Pain Research and was supported by the EveryCat Foundation (formerly the Winn Feline Foundation) under grant W18-028 and the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases under award 079713. Joshua Wheeler, postdoctoral student at NC State, is first author. Other NC State collaborators include Margaret Gruen, professor of clinical sciences; and former postdoctoral student Chie Mochizuki, who is currently at the University of Tennessee.

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