Osteoarthritis, the most common joint disease affecting millions of people, has long been a challenge to treat. Until now, there have been no methods that simultaneously prevent joint degeneration and reduce pain associated with osteoarthritis.

In a groundbreaking development, Yale and VA researchers have identified Nav1.7 sodium channels as a novel target for the development of disease-modifying treatments for osteoarthritis.

The findings were published in today’s issue of the journal Nature.

For decades, scientists have understood that specialized molecules known as sodium channels power 'excitable' cells like nerve cells, muscle cells, and heart cells to generate electrical signals. While smaller quantities of sodium channels exist in non-excitable cells, their roles have remained a mystery.

Now, Yale and VA researchers report that small numbers of Nav1.7 channels play a key role in controlling the behavior of non-excitable cells in osteoarthritis.

The study began with the discovery that Nav1.7 channels exist and function in chondrocytes of patients with osteoarthritis. Chondrocytes are the collagen-producing cells responsible for maintaining joint integrity. Building upon this unexpected finding, the researchers showed that deletion of Nav1.7, through genetic manipulation from mouse chondrocytes, substantially reduces joint damage and associated pain in two separate models of osteoarthritis.

The researchers further demonstrated that drugs that block Nav1.7 channels, including carbamazepine, a sodium channel blocker currently used to treat epilepsy and trigeminal neuralgia, provides substantial protection from joint damage and associated pain in the two models.

The study was led by Chuan-Ju Liu, the Charles W. Ohse Professor of Orthopedics and Stephen G. Waxman, Bridget M. Flaherty professor of neurology and professor of neurobiology and of pharmacology at Yale School of Medicine, and director of the VA Rehabilitation Research Center at VA West Haven.

“Discovery that Nav1.7 controls chondrocyte behavior in osteoarthritis, with a strong impact on cartilage homeostasis, opens new avenues for disease-modifying treatments,” noted Wenyu Fu, first author of the study and research scientist in the Liu laboratory.

The identification of Nav1.7 in osteoarthritis-associated chondrocytes uncovers a promising and previously unexplored approach for the development of disease-modifying treatments that slow or prevent joint damage.

“Sodium channels have been a centerpiece of bioelectricity since their discovery in 1952,” said Waxman. “Their roles in nerve impulse generation are understood in exquisite detail, and they have served as therapeutic targets for multiple diseases of 'excitable' tissues such as nerve, muscle, and the heart. Less well appreciated is the occurrence of sodium channels, in much lower numbers, in non-excitable tissues, as we had shown in the 1990s. This study provides a window on how small numbers of sodium channels can regulate the behavior of non-excitable cells.”

“Their strong role in modulating the function of these cells raises the exciting possibility of a new therapeutic approach to halt or slow the progression of osteoarthritis,” added Liu. “A next step will be to assess new therapeutic strategies aimed at blocking Nav1.7 channels, or gene therapy approaches that knock down the production of these channels.”

The discovery is particularly critical as relief from osteoarthritis represents an immense unmet need. According to the CDC, the disease affects over 32.5 million US adults.