Researchers at Stanford Medicine have identified a treatment that restores damaged knee cartilage in aging mice and prevents arthritis from developing after serious joint injuries, offering a potential alternative to the hundreds of thousands of joint replacement surgeries performed each year in the United States.
The approach targets a protein called 15-PGDH, which accumulates with age and contributes to tissue decline throughout the body. When researchers blocked this protein in older mice, cartilage that had thinned and weakened with age grew back thicker and regained function.
The findings also extended to human tissue. Cartilage samples taken from patients undergoing knee replacement surgery began regenerating new cartilage when exposed to the treatment in the laboratory.
Osteoarthritis affects roughly one in five American adults and costs the health system approximately 65 billion dollars annually. The disease gradually destroys the smooth cartilage lining joints, causing pain, stiffness, and swelling. Currently, no approved medication can reverse the underlying damage, leaving doctors to manage symptoms with pain relievers or recommend surgery when the condition becomes severe.
The new treatment works by blocking what researchers call a "gerozyme," a class of proteins that become more abundant as people age and drive the decline of multiple tissue types. The same team that discovered gerozymes in 2023 previously showed that blocking 15-PGDH restored muscle mass and endurance in older animals and improved regeneration of bone, nerve, and blood cells.
Scientists tested the 15-PGDH inhibitor in mice with knee injuries mimicking ACL tears, a common sports injury that often leads to osteoarthritis. Mice receiving the treatment twice weekly for four weeks after injury rarely developed arthritis, while untreated animals developed the disease within that timeframe. Treated mice also walked more normally and bore more weight on their injured legs.
The discovery challenges conventional assumptions about how cartilage repairs itself. Instead of relying on stem cells to generate new tissue, cartilage cells called chondrocytes appear capable of shifting their genetic activity and returning to a younger, healthier state.
"This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to aging or injury," said Helen Blau, director of the Baxter Laboratory for Stem Cell Biology at Stanford. "We were looking for stem cells, but they are clearly not involved."
Researchers compared cartilage from young and old mice and found that 15-PGDH levels roughly doubled with age. When they blocked the protein in older animals, the composition of cartilage cells shifted dramatically. One group of cells responsible for cartilage breakdown dropped from 8 percent to 3 percent of the population. Meanwhile, cells involved in building healthy cartilage increased from 22 percent to 42 percent.
The treatment operates by increasing prostaglandin E2, a molecule critical for tissue regeneration. In the past, researchers focused on prostaglandin E2 because it contributes to inflammation and pain. The new work shows that at normal biological levels, the molecule actually promotes regeneration.
An oral version of the 15-PGDH inhibitor is already undergoing clinical trials for age-related muscle weakness and has demonstrated safety in healthy volunteers. Researchers plan to launch trials testing the drug's effect on cartilage regeneration in people with arthritis.
The study was published in the journal Science and conducted with collaborators from the Sanford Burnham Prebys Medical Discovery Institute. Nidhi Bhutani, associate professor of orthopedic surgery, and her colleagues examined how the treatment affects the largest group of cartilage cells involved in building and maintaining the extracellular matrix, the scaffold that gives cartilage its structure and function.
Some of the Stanford researchers involved in the work hold financial interests related to the technology. The university has filed patent applications for 15-PGDH inhibition that have been licensed to Epirium Bio, a company that includes Stanford investigators among its founders and investors.
Author Jessica Williams: "If this treatment works in humans the way it does in mice, doctors could stop chasing joint replacements and start fixing the actual problem, which changes the entire game for millions of people living with arthritis."
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