Researchers also found encouraging results in human tissue. Samples collected during knee replacement surgeries began producing new, functional cartilage when exposed to the treatment.

The findings raise the possibility that damaged cartilage caused by aging or osteoarthritis could one day be repaired with either a local injection or an oral medication. If successful in people, the approach could reduce the need for knee and hip replacement surgeries.

An oral version of the treatment is already being tested in clinical trials for age-related muscle weakness.

Targeting the Root Cause of Osteoarthritis

Osteoarthritis is the most common form of arthritis and affects about one in five adults in the United States. The disease gradually breaks down cartilage in the joints, causing pain, stiffness, and swelling. It is estimated to generate roughly $65 billion in direct health care costs each year.

Current treatments focus mainly on pain relief and, in severe cases, joint replacement surgery. No approved medication can slow, stop, or reverse the underlying disease process.

The new treatment works by blocking a protein called 15-PGDH, which researchers describe as a "gerozyme." This class of proteins becomes more abundant with age and contributes to declining tissue function throughout the body.

The same research team first identified gerozymes in 2023. Previous studies showed that 15-PGDH plays a major role in age-related muscle decline in mice. When researchers block the protein, older animals gain muscle mass and endurance. When the protein is artificially increased in young mice, their muscles become weaker and smaller.

Scientists have also linked 15-PGDH to the regeneration of bone, nerve, and blood cells.

A Different Type of Tissue Regeneration

In many tissues, regeneration occurs because stem cells multiply and develop into new specialized cells. Cartilage appears to work differently.

Instead of relying on stem cells, cartilage-producing cells called chondrocytes seem able to shift their gene activity and return to a more youthful 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, PhD, professor of microbiology and immunology. "We were looking for stem cells, but they are clearly not involved. It's very exciting."

Blau, director of the Baxter Laboratory for Stem Cell Biology and the Donald E. and Delia B. Baxter Foundation Professor, and Nidhi Bhutani, PhD, associate professor of orthopedic surgery, are the senior authors of the study, which was published in Science. Instructor of orthopedic surgery Mamta Singla, PhD, and former postdoctoral scholar Yu Xin (Will) Wang, PhD, are the lead authors. Wang is now an assistant professor at the Sanford Burnham Institute in San Diego.

Remarkable Cartilage Regrowth

"Millions of people suffer from joint pain and swelling as they age," Bhutani said. "It is a huge unmet medical need. Until now, there has been no drug that directly treats the cause of cartilage loss. But this gerozyme inhibitor causes a dramatic regeneration of cartilage beyond that reported in response to any other drug or intervention."

The human body contains three main forms of cartilage. Elastic cartilage provides flexibility in structures such as the outer ear. Fibrocartilage is tough and shock-absorbing, found in places like the discs between vertebrae. Hyaline cartilage is smooth and slippery, allowing joints such as the knees, hips, shoulders, and ankles to move freely.

Osteoarthritis primarily damages hyaline cartilage, also called articular cartilage.

As joints age or experience injury or excess stress from obesity, chondrocytes begin producing inflammatory molecules and breaking down collagen, the main structural component of cartilage. As collagen disappears, cartilage becomes thinner and softer. Inflammation then triggers the pain and swelling associated with osteoarthritis.

Unlike many other tissues, articular cartilage rarely repairs itself. While researchers have identified possible cartilage-producing stem cells in bone, similar cells have not been successfully identified in articular cartilage.

Why Researchers Focused on 15-PGDH

Earlier work from Blau's laboratory showed that prostaglandin E2 is critical for muscle stem cell function. The protein 15-PGDH breaks down prostaglandin E2.

When researchers inhibit 15-PGDH or increase prostaglandin E2 levels, damaged muscle, nerve, bone, colon, liver, and blood tissues regenerate more effectively in young mice.

The team wondered whether the same mechanism might influence cartilage aging.

When they compared cartilage from young and old mice, they found that levels of 15-PGDH approximately doubled with age.

To test the idea, researchers treated older mice with a small molecule drug that blocks 15-PGDH activity. Some animals received injections into the abdomen, exposing the whole body to the treatment. Others received injections directly into the knee joint.

Both approaches produced striking results. Cartilage that had become thinner and less functional with age grew thicker across the joint surface. Additional testing showed the regenerated tissue was hyaline cartilage, the type needed for healthy joint function, rather than the less effective fibrocartilage.

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

Preventing Arthritis After ACL-Type Injuries

The researchers also investigated whether the treatment could protect joints after injury.

They used a mouse model that mimics ACL tears, a common sports injury seen in activities such as soccer, basketball, and skiing that involve sudden stopping, pivoting, or jumping.

Although ACL injuries can be surgically repaired, roughly half of affected people develop osteoarthritis in the injured joint within about 15 years.

Mice that received the gerozyme inhibitor twice weekly for four weeks after injury were far less likely to develop osteoarthritis. In contrast, untreated animals showed 15-PGDH levels that were about twice as high as those of uninjured mice and developed osteoarthritis within four weeks.

Treated mice also walked more normally and placed more weight on the injured limb.

"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."

Reprogramming Aging Cartilage Cells

A closer look at cartilage cells revealed important differences between young and old joints.

Older chondrocytes were more likely to activate genes linked to inflammation and unwanted conversion of cartilage into bone. They were less likely to express genes associated with healthy cartilage formation.

The treatment appeared to reverse many of these age-related changes.

One group of chondrocytes that produced 15-PGDH and expressed genes involved in cartilage breakdown dropped from 8% of cells to 3% after treatment. Another group associated with fibrocartilage production fell from 16% to 8%.

Meanwhile, a population of cells involved in building hyaline cartilage and maintaining the extracellular matrix increased from 22% to 42%.

Overall, the results suggest the treatment shifts cartilage toward a younger, healthier state without requiring stem or progenitor cells.

Human Cartilage Also Responded

The team then examined cartilage removed from people undergoing total knee replacement surgery for osteoarthritis.

After one week of treatment with the 15-PGDH inhibitor, the tissue showed fewer cartilage-degrading cells and lower activity of genes linked to cartilage breakdown and fibrocartilage production. The samples also began generating new articular cartilage.

"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. And by targeting these cells for regeneration, we may have an opportunity to have a bigger overall impact clinically."

Blau added, "Phase 1 clinical trials of a 15-PGDH inhibitor for muscle weakness have shown that it 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. We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement."

Researchers from the Sanford Burnham Prebys Medical Discovery Institute also contributed to the study.

The research was funded by the National Institutes of Health (grants R01AR070864, R01AR077530, R01AG069858 and R00NS120278), the Baxter Foundation for Stem Cell Biology, the Li Ka Shing Foundation, the Stanford Cardiovascular Institute, the Milky Way Research Foundation, the Canadian Institutes of Health Research, a Stanford Translational Research and Applied Medicine Pilot grant, a GlaxoSmithKline Sir James Black Postdoctoral Fellowship, and a Stanford Dean's Postdoctoral Fellowship.

Blau, Bhutani, and several co-authors are inventors on Stanford University patent applications involving 15-PGDH inhibition for cartilage repair and tissue rejuvenation that have been licensed to Epirium Bio. Blau is a co-founder of Myoforte/Epirium and holds equity and stock options in the company.