A Stanford Medicine led study has found that an injection that blocks the activity of a protein linked to aging can reverse naturally occurring cartilage loss in the knee joints of older mice. The treatment also prevented arthritis from developing after knee injuries resembling ACL tears commonly seen in athletes and active individuals. Notably, an oral form of the treatment is already in clinical trials for age-related muscle weakness.

Human tissue samples from knee replacement surgeries including the extracellular matrix and cartilage-producing chondrocytes also responded positively, generating new, functional cartilage when exposed to the treatment.

These findings suggest that it may be possible to restore cartilage lost to aging or arthritis with an oral medication or a localized injection, potentially eliminating the need for knee or hip replacement surgeries in the future.

The therapy targets the root cause of osteoarthritis, a degenerative joint disease affecting one in five adults in the United States and costing over $65 billion annually. Currently, no medication can slow or reverse osteoarthritis; treatment options focus mainly on pain relief and joint replacement surgery.

The protein 15-PGDH referred to as a gerozyme due to its increased activity with age is a key regulator of aging processes. Gerozymes, first identified by the same research team in 2023, contribute to the decline in tissue function. Blocking 15-PGDH with a small molecule has been shown to boost muscle mass and endurance in older mice, while increasing the protein in young mice leads to muscle weakening. The protein has also been linked to regeneration of bone, nerve, and blood cells.

In many tissues, regeneration occurs through increased activity of tissue-specific stem cells. However, in cartilage, chondrocytes instead revert to a more youthful gene expression profile without stem cell involvement.

“This represents a new mechanism for regenerating adult tissue and holds major clinical promise for treating arthritis from aging or injury,” said Helen Blau, PhD, professor of microbiology and immunology. “We initially looked for stem cells, but it’s clear they’re not involved. It’s incredibly exciting.”

‘Dramatic regeneration’

“Millions of people experience joint pain and swelling as they age,” Bhutani said. “This represents a major unmet medical need. Until now, no drug has directly addressed the root cause of cartilage loss. But this inhibitor of the gerozyme triggers a dramatic regeneration of cartilage unlike anything previously reported.”

The human body contains three main types of cartilage: elastic, fibrocartilage, and hyaline. Hyaline (articular) cartilage the smooth, friction-reducing tissue in joints is the type most affected by osteoarthritis. When joints are stressed by aging, injury, or obesity, chondrocytes begin releasing inflammatory molecules and degrading collagen, causing cartilage thinning, joint swelling, and pain. Under normal conditions, articular cartilage has very limited capacity to regenerate, and attempts to identify stem cells within it have largely failed.

Earlier work from Blau’s group showed that prostaglandin E2 is essential for muscle stem cell function and is degraded by 15-PGDH. Inhibiting 15-PGDH boosts prostaglandin E2 levels, supporting regeneration of multiple tissues in young mice.

The team suspected that the same pathway might influence cartilage aging and injury. They found that levels of 15-PGDH in knee cartilage doubled with age. Treating older mice with a 15-PGDH inhibitor either systemically or through direct joint injection significantly thickened their cartilage, restoring it to a more youthful state. Further testing confirmed that chondrocytes were producing functional hyaline cartilage, not the less optimal fibrocartilage.

“The degree of cartilage regeneration in aged mice was unexpected,” Bhutani said. “The improvement was truly remarkable.”

Source: https://med.stanford.edu/news/all-news/2025/11/joint-cartilage-aging.html