STANFORD, Calif., May 8, 2024 — Imagine a future where worn-out knees can be rebuilt from within, not replaced with metal and plastic. A new study out of Stanford Medicine suggests that’s not science fiction. Researchers have discovered that blocking a protein linked to aging can actually reverse cartilage loss in older mice, and even prevent arthritis from developing after injuries similar to ACL tears.
A Potential Game-Changer for Joint Health
Table of Contents
The findings offer a new approach to treating osteoarthritis, a debilitating condition affecting millions.
- Osteoarthritis affects roughly one in five adults in the U.S.
- The study identified a protein, 15-PGDH, as a key driver of cartilage loss.
- Blocking this protein led to cartilage regeneration in mice, even after injury.
- Human cartilage samples also showed positive responses to the treatment.
- Clinical trials are already underway testing an oral version of the treatment for muscle weakness.
The research, published in the journal Science, offers a fundamentally different approach to tackling osteoarthritis. Currently, treatments largely focus on managing pain or, as a last resort, surgically replacing damaged joints. But this new work targets the cause of cartilage breakdown, potentially offering a way to restore what’s been lost.
Unlocking the Secrets of Cartilage Regeneration
“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, PhD, professor of microbiology and immunology. “We were looking for stem cells, but they are clearly not involved. It’s very exciting.”
At the heart of the discovery is a protein called 15-PGDH. Researchers have dubbed it a “gerozyme” – a type of enzyme whose levels increase with age and contribute to tissue decline. The team first identified gerozymes in 2023, noting their role in the gradual loss of tissue function. In mice, higher levels of 15-PGDH were linked to declining muscle strength. Blocking the enzyme boosted muscle mass and endurance in older animals.
But the surprising twist? Cartilage seems to respond to this treatment in a unique way. Unlike most tissues that rely on stem cells for repair, cartilage appears to reprogram its existing cells, shifting them into a more youthful state.
How Does It Work? A Shift in Cellular Behavior
Researchers found that chondrocytes – the cells responsible for maintaining cartilage – change their gene expression when 15-PGDH is blocked. Specifically, cells producing inflammatory molecules and breaking down collagen decreased, while those promoting cartilage formation increased. One group of chondrocytes that produced 15-PGDH and cartilage-degrading genes dropped from 8% to 3%, while a population associated with hyaline cartilage formation rose from 22% to 42%.
This cellular shift was observed in both aged mice and those with injuries mimicking ACL tears – a common sports injury that often leads to osteoarthritis. Mice treated with the 15-PGDH inhibitor showed significant cartilage regeneration and improved mobility. “Cartilage regeneration to such an extent in aged mice took us by surprise,” said Nidhi Bhutani, PhD, associate professor of orthopaedic surgery. “The effect was remarkable.”
Promising Results in Human Tissue
The findings aren’t limited to mice. When researchers tested the inhibitor on human cartilage samples taken from knee replacement surgeries, they observed similar positive changes: fewer 15-PGDH-producing cells and early signs of cartilage regeneration.
Osteoarthritis develops when joints are stressed by aging, injury, or obesity. Chondrocytes release inflammatory molecules, breaking down collagen – the main structural protein in cartilage. As collagen diminishes, cartilage thins and softens, leading to pain and swelling. Under normal circumstances, articular cartilage has limited ability to regenerate.
The Role of Prostaglandin E2
This research builds on earlier work from Blau’s lab, which showed that prostaglandin E2 is crucial for muscle stem cell function. The enzyme 15-PGDH breaks down prostaglandin E2. By blocking 15-PGDH, researchers previously supported the repair of damaged muscle, nerve, bone, colon, liver, and blood cells in young mice. This led them to investigate whether the same pathway could be applied to cartilage.
The team discovered that 15-PGDH levels roughly doubled in knee cartilage as mice aged. Blocking the enzyme, either systemically or directly in the knee joint, led to cartilage thickening.
What’s Next?
Phase 1 clinical trials of a 15-PGDH inhibitor for muscle weakness have already shown the drug is safe and active in healthy volunteers. “Our hope is that a similar trial will be launched soon to test its effect in cartilage regeneration,” Blau said. “We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement.”
Mamta Singla, PhD, instructor of orthopaedic surgery, and Yu Xin (Will) Wang, PhD, formerly a postdoctoral scholar at Stanford and now an assistant professor at the Sanford Burnham Institute in San Diego, served as lead authors of the study.
