New research findings in mice suggest that drugs that inhibit a key protein involved in the pain response, such as the anti-epileptic and bipolar disorder drug carbamazepine, may be effective at slowing the progression of osteoarthritis.
In an article published Jan. 3 in Nature, researchers from Yale University described how they discovered that chondrocytes—cells that make up healthy cartilage—have the same type of sodium channels that are found on neurons involved in the pain response. They also showed that blocking one of these channels, Nav1.7, in mice could not only alleviate pain associated with osteoarthritis but also prevent the disease from getting worse.
“Our identification of Nav1.7 as a dual target for disease modification and pain relief marks a significant advancement in devising a novel therapeutic approach to impede or decelerate the progression of osteoarthritis while concurrently alleviating associated pain,” senior author Chuan-Ju Lu, Ph.D. told Fierce Biotech Research in an email.
Nav1.7 is one of nine voltage-gated sodium ion channels that produce nerve impulses in cells like neurons, muscle cells and heart cells—in other words, “excitable” cells, as senior author Stephen Waxman, M.D., Ph.D. described in an email. Nav1.7 in particular has generated research interest as a target for pain relief because it acts as a “‘volume knob’ for pain signaling,” as Waxman put it.
But researchers have known since the 1990s that sodium ion channels aren’t exclusive to excitable cells. They’re also found in low densities on other types of cells, such as epithelial cells.
“The presence of [sodium ion channels] in non-excitable cells has drawn less attention, because the function of these channels has not been known, and most of the work on non-excitable cells has been done in vitro,” Waxman explained to FBR.
Thus, it was “somewhat unexpected” when an RNA sequencing screen to identify novel genes associated with osteoarthritis turned up one that encodes Nav1.7, Lu recalled. While there weren’t as many Nav1.7 channels in the chondrocytes as there were in neurons associated with pain—just 400 channels per chondrocyte compared to 150,000 within a neuron, Waxman said—the ones that were present were functional.
“The low density of Nav channels within these cells…made this study very challenging,” he explained. “But our recordings showed that the channels are present within chondrocytes, where they have normal biophysical properties” and control the cells’ behavior, he added.
Subsequent experiments on mouse models of osteoporosis showed that removing the gene for Nav1.7 in chondrocytes not only improved the animals’ pain but also stopped cartilage degeneration. That led the researchers to see if carbamazepine—a nonspecific sodium ion channel inhibitor marketed by Novartis as Tegretol—might be effective against the condition. The drug protected the mice from joint damage.
The researchers still need to figure out why the relatively small number of sodium ion channels are enough to have an effect on chondrocytes, Waxman said, as well as to learn how different types of sodium channel inhibitors delivered via different routes affect chondrocytes and mice with osteoarthritis.
“Translation from animal models to humans is not easy,” he said. “There is still a lot to do, but we are hopeful that this work may open up a new therapeutic approach that would prevent the progression of osteoarthritis,” he said.