The Stanford team built on earlier findings from Blau's lab: 15-PGDH breaks down a molecule called prostaglandin E2, which supports regeneration in muscle, nerve, bone, colon, liver and blood cells. They tested whether the same pathway governs cartilage aging.

The researchers gave older mice the 15-PGDH inhibitor two ways: injected into the abdomen for a body-wide effect, or delivered directly into the knee joint. Both worked. Cartilage that had been thinner and less functional in old animals became thicker across the joint surface — and crucially, the cells produced hyaline cartilage, the type joints need, rather than the less suitable fibrocartilage.

"Cartilage regeneration to such an extent in aged mice took us by surprise," Bhutani said. "The effect was remarkable."

Can it protect knees after injury?

The team also simulated ACL tears — injuries common in soccer, basketball and skiing. About 50% of people with such injuries develop osteoarthritis in the affected joint within roughly 15 years, even after successful ligament surgery.

In the mouse experiments, researchers gave the inhibitor twice a week for four weeks after injury. The results were stark:

• Control mice showed 15-PGDH levels twice those of uninjured animals and developed osteoarthritis within four weeks.
• Treated mice developed osteoarthritis far less often.
• They also moved more normally and put more weight on the injured leg than untreated animals did.

"Interestingly, prostaglandin E2 has been implicated in inflammation and pain," Blau said. "But this research shows that, at normal biological levels, small increases in prostaglandin E2 can promote regeneration."

What happened inside the cells?

Instead of recruiting stem cells, the treatment reprogrammed existing cartilage cells called chondrocytes. Genetic analysis of three cell populations showed a clear shift toward a younger state:

• Cells producing 15-PGDH and expressing degradation-related genes fell from 8% to 3%.
• A fibrocartilage-linked population dropped from 16% to 8%.
• Cells expressing genes for hyaline cartilage and a healthy extracellular matrix — the protein network giving tissue its structure — rose from 22% to 42%.

"The mechanism is quite striking and really shifted our perspective about how tissue regeneration can occur," Bhutani said. "It's clear that a large pool of already existing cells in cartilage are changing their gene expression patterns."

Did human cartilage respond?

Yes, in laboratory samples. Cartilage taken from osteoarthritis patients undergoing total knee replacement was treated with the inhibitor for one week. The tissue showed fewer 15-PGDH-producing chondrocytes, reduced activity in genes linked to cartilage breakdown, and the beginnings of articular cartilage regeneration.

What are the limitations?

These are early findings. The results come from mice and from human tissue in a dish — not from patients. The study does not establish that the treatment can regrow cartilage or prevent osteoarthritis in people, and clinical trials testing cartilage regeneration specifically will be needed to confirm safety and effectiveness.

There is a promising sign, though. An oral 15-PGDH inhibitor has already reached human testing for a different age-related condition, muscle weakness. "Phase 1 clinical trials of a 15-PGDH inhibitor for muscle weakness have shown that it is safe and active in healthy volunteers," Blau said. "Our hope is that a similar trial will be launched soon to test its effect in cartilage regeneration."

The lead authors are Mamta Singla, PhD, and Yu Xin (Will) Wang, PhD, now at the Sanford Burnham Institute in San Diego. The work was funded primarily by the National Institutes of Health. Blau, Bhutani and coauthors hold patent applications related to 15-PGDH inhibition that are licensed to Epirium Bio, a company in which Blau holds equity — a standard disclosure for translational research of this kind.