Stanford scientists found a way to regrow cartilage and stop arthritis

Human cartilage samples taken from knee replacement surgeries also responded positively. These samples included both the supportive extracellular matrix of the joint and cartilage-producing chondrocyte cells. When treated, the tissue began forming new, functional cartilage.

Together, the findings suggest that cartilage lost due to aging or arthritis may one day be restored using either a pill or a targeted injection. If successful in people, such treatments could reduce or even eliminate the need for knee and hip replacement surgery.

A Direct Attack on Osteoarthritis

Osteoarthritis is a degenerative joint disease that affects about one in five adults in the United States and generates an estimated $65 billion each year in direct health care costs. Current treatments focus on managing pain or replacing damaged joints surgically. There are no approved drugs that can slow or reverse the underlying cartilage damage.

The new approach targets the root cause of the disease rather than its symptoms, offering a potential shift in how osteoarthritis is treated.

The Role of a Master Aging Enzyme

The protein at the center of the study is called 15-PGDH. Researchers refer to it as a gerozyme because its levels increase as the body ages. Gerozymes were identified by the same research team in 2023 and are known to drive the gradual loss of tissue function.

In mice, higher levels of 15-PGDH are linked to declining muscle strength with age. Blocking the enzyme using a small molecule boosted muscle mass and endurance in older animals. In contrast, forcing young mice to produce more 15-PGDH caused their muscles to shrink and weaken. The protein has also been connected to regeneration in bone, nerve, and blood cells.

In most of these tissues, repair happens through the activation and specialization of stem cells. Cartilage appears to be different. In this case, chondrocytes change how their genes behave, shifting into a more youthful state without relying on stem cells.

A New Path to Tissue 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.”

Blau, who leads the Baxter Laboratory for Stem Cell Biology and holds the Donald E. and Delia B. Baxter Foundation Professorship, and Nidhi Bhutani, PhD, associate professor of orthopaedic surgery, are the study’s senior authors. The research was published in Science. Mamta Singla, PhD, instructor of orthopaedic surgery, and former postdoctoral scholar Yu Xin (Will) Wang, PhD, served as lead authors. Wang is now an assistant professor at the Sanford Burnham Institute in San Diego.

Dramatic Regeneration of Joint Cartilage

“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 types of cartilage. Elastic cartilage is soft and flexible and forms structures such as the outer ear. Fibrocartilage is dense and tough, helping absorb shock in places like the spaces between spinal vertebrae. Hyaline cartilage is smooth and glossy, allowing joints such as the hips, knees, shoulders, and ankles to move with low friction. This type, also called articular cartilage, is the form most commonly damaged in osteoarthritis.

Why Cartilage Rarely Grows Back

Osteoarthritis develops when joints are stressed by aging, injury, or obesity. Chondrocytes begin releasing inflammatory molecules and breaking down collagen, the main structural protein in cartilage. As collagen is lost, cartilage becomes thinner and softer. Inflammation then leads to swelling and pain, which are hallmarks of the disease.

Under normal conditions, articular cartilage has very limited ability to regenerate. While some stem or progenitor cells capable of forming cartilage have been identified in bone, similar cells have not been successfully found within articular cartilage itself.

Connecting Aging, Prostaglandins, and Repair

Earlier research from Blau’s lab showed that prostaglandin E2 is essential for muscle stem cell function. The enzyme 15-PGDH breaks down prostaglandin E2. By blocking 15-PGDH or increasing prostaglandin E2 levels, researchers previously supported the repair of damaged muscle, nerve, bone, colon, liver, and blood cells in young mice.

This led the team to question whether the same pathway might be involved in cartilage aging and joint damage. When they compared knee cartilage from young and old mice, they found that 15-PGDH levels roughly doubled with age.

Regrowing Cartilage in Aging Knees

Researchers then injected older mice with a small molecule that inhibits 15-PGDH. They first administered the drug into the abdomen to affect the entire body, and later injected it directly into the knee joint. In both cases, cartilage that had become thin and dysfunctional with age thickened across the joint surface.

Additional tests confirmed that the regenerated tissue was hyaline cartilage rather than the less functional fibrocartilage.

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

Protecting Joints After ACL-Like Injuries

The team observed similar benefits in mice with knee injuries resembling ACL tears, which often occur during sports involving sudden stopping, pivoting, or jumping. Although such injuries can be surgically repaired, about half of affected people develop osteoarthritis in the injured joint within 15 years.

Mice that received twice-weekly injections of the gerozyme inhibitor for four weeks after injury were far less likely to develop osteoarthritis. In contrast, animals given a control treatment had double the levels of 15-PGDH compared with uninjured mice and developed osteoarthritis within four weeks.

Treated mice also moved more normally and placed more weight on the injured leg than untreated animals.

“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 Cartilage Cells Without Stem Cells

Closer analysis showed that chondrocytes in older mice expressed more genes linked to inflammation and the conversion of cartilage into bone, along with fewer genes involved in cartilage formation. Treatment shifted these patterns.

One group of chondrocytes that produced 15-PGDH and cartilage-degrading genes dropped from 8% to 3%. Another group associated with fibrocartilage formation declined from 16% to 8%. A third population, which did not produce 15-PGDH and instead expressed genes tied to hyaline cartilage formation and maintenance of the extracellular matrix, rose from 22% to 42%.

These changes indicate a broad return to a more youthful cartilage profile without involving stem or progenitor cells.

Evidence From Human Cartilage Samples

The researchers also tested cartilage taken from patients undergoing total knee replacement for osteoarthritis. After one week of treatment with the 15-PGDH inhibitor, the tissue showed fewer 15-PGDH-producing chondrocytes, reduced expression of cartilage degradation and fibrocartilage genes, and early signs of articular cartilage regeneration.

“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.”

Looking Toward Human Trials

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 work was supported by funding from 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 other co-authors are inventors on patent applications held by Stanford University related to 15-PGDH inhibition in cartilage and tissue rejuvenation, which are licensed to Epirium Bio. Blau is a co-founder of Myoforte/Epirium and holds equity and stock options in the company.