The treatment also showed promise in human tissue. Cartilage samples taken during knee replacement surgery began producing new, functional articular cartilage after exposure to a 15-PGDH inhibitor.

Together, the findings suggest that cartilage damaged by aging or osteoarthritis may retain more capacity for repair than previously believed. If the approach proves safe and effective in people, it could eventually lead to oral medications or injections designed to regenerate cartilage and reduce the need for knee and hip replacement surgery.

Targeting the biological cause of osteoarthritis

Osteoarthritis is a degenerative joint disease in which cartilage gradually breaks down. The condition can cause pain, swelling, stiffness, and difficulty moving. It affects approximately one in five adults in the United States and is estimated to account for about $65 billion in direct medical costs each year.

Current treatments mainly manage pain and other symptoms. When osteoarthritis becomes severe, joint replacement may be the only remaining option. No drug can currently reliably slow or reverse the disease itself.

The Stanford Medicine-led study focused on 15-PGDH, a protein that becomes more abundant with age and contributes to the gradual loss of tissue function. The researchers describe 15-PGDH as a “gelozyme,” a term for enzymes that increase with age and contribute to tissue deterioration.

Earlier studies from the same research group found that 15-PGDH regulates aging in several tissues. Blocking the protein with a small molecule increased muscle mass and endurance in older mice, while increasing 15-PGDH in young animals caused muscles to contract and weaken. The protein is also believed to influence the regeneration of bone, nerves, and blood cells.

Many tissues heal through tissue-specific stem cells that multiply and develop into specialized cells. Cartilage appears to work differently. Rather than relying on stem cells, existing cartilage cells called chondrocytes changed their gene activity and returned to a more youthful state.

“This is a new way to regenerate adult tissue and holds great clinical promise for the treatment of age- and injury-related arthritis,” said Dr. Helen Blau, professor of microbiology and immunology. “We were looking for stem cells, and it’s clear that stem cells are not involved. We’re very excited.”

Blau, director of the Baxter Institute for Stem Cell Biology and Donald E. Baxter and Delia B. Baxter Foundation Professor, and Dr. Nidhi Bhutani, associate professor of orthopedic surgery, are senior authors of the study. Dr. Mamta Singla, a lecturer in orthopedic surgery, and Dr. Yu-Xin (Will) Wang, a former postdoctoral fellow, are the study’s lead authors. Wang is currently an assistant professor at the Sanford Burnham Prebys Medical Discovery Institute in San Diego.

15-PGDH inhibitor produces “drastic regeneration” of cartilage

“Millions of people suffer from joint pain and swelling as they age,” Bhutani said. “This is a major unmet medical need. Until now, there have been no drugs that directly treat the cause of cartilage loss. However, this gelozyme inhibitor causes dramatic cartilage regeneration that exceeds what has been reported in response to other drugs or interventions.”

There are three main types of cartilage in the human body, each with a different function.

• Elastic cartilage is flexible and helps form structures such as the outer ear.
• Fibrocartilage is strong and helps absorb force, including between the vertebrae of the spine.
• Hyaline cartilage is smooth and slippery, allowing bones to move with little friction in joints such as the ankles, hips, shoulders, and knees.

Hyaline cartilage in the joints is also called articular cartilage. It is the type most commonly damaged by osteoarthritis.

Osteoarthritis can develop when joints are affected by aging, injury, or obesity. Cartilage cells begin producing inflammatory molecules and breaking down collagen, the structural protein that gives cartilage much of its strength.

As collagen is lost, cartilage becomes thinner and softer. Inflammation contributes to swelling and pain, two common symptoms of osteoarthritis.

Articular cartilage usually has limited ability to repair itself. Although researchers have identified stem or progenitor cells within bone that may be able to form cartilage, efforts to find similar cell populations within articular cartilage have been unsuccessful.

Blocking an age-related protein restores youthful cartilage activity

Previous research from Blau’s laboratory found that prostaglandin E2 is important for muscle stem cell function. The protein 15-PGDH breaks down prostaglandin E2.

Blocking 15-PGDH or increasing prostaglandin E2 levels has been shown to promote the regeneration of damaged muscle, nerve, bone, colon, liver, and blood cells in young mice.

These findings led the researchers to investigate whether the same biological pathway contributes to cartilage deterioration as animals age and recover from injury.

When the researchers compared knee cartilage from young and old mice, they found that 15-PGDH levels roughly doubled with age.

They then gave older mice small-molecule drugs designed to inhibit 15-PGDH. In one experiment, the drug was injected into the abdomen to affect the whole body. In another, it was injected directly into the knee joint.

Both approaches produced significant results. Before treatment, the knee cartilage of older mice was thinner and less functional than the cartilage of young animals. After treatment, the entire joint surface became thicker.

Importantly, the regenerated tissue was hyaline cartilage—the smooth articular cartilage needed for healthy joint movement—rather than fibrocartilage, which is less suitable for that function.

“We were surprised that cartilage regenerated to such an extent in older mice,” Bhutani said. “The effect was noticeable.”

Cartilage treatment protects mice after ACL-like knee injuries

The researchers also tested whether blocking 15-PGDH could protect joints after trauma.

ACL tears are common in sports such as soccer, basketball, and skiing, where athletes frequently rotate, stop suddenly, or jump. Although surgery can repair the torn ligament, repairing the immediate injury does not necessarily prevent long-term joint damage.

Approximately 50% of people who experience these injuries develop osteoarthritis in the affected joint within about 15 years.

In the mouse experiments, researchers administered a 15-PGDH inhibitor twice a week for four weeks after injury. The treatment dramatically reduced the likelihood that the animals would develop osteoarthritis.

Mice given the control drug had twice the 15-PGDH levels of mice with uninjured knees and developed osteoarthritis within four weeks. Treated mice moved more normally and placed more weight on the foot connected to the injured leg than untreated animals.

“Interestingly, prostaglandin E2 is thought to be involved in inflammation and pain,” Blau said. “However, this study shows that at normal biological levels, small increases in prostaglandin E2 can promote regeneration.”

15-PGDH inhibition rejuvenates older cartilage cells

To understand how the treatment worked, the researchers examined cartilage cells from young and old mice.

Older chondrocytes showed increased activity in genes associated with inflammation and the undesirable conversion of hyaline cartilage to bone. At the same time, genes involved in normal cartilage development were less active.

Treatment reversed that balance. One group of older chondrocytes that produced 15-PGDH and expressed genes associated with cartilage breakdown fell from 8% to 3% of the cells.

A second group that did not produce 15-PGDH but expressed genes associated with fibrocartilage formation decreased from 16% to 8%.

A third group increased from 22% to 42%. These cells did not produce 15-PGDH and expressed genes involved in hyaline cartilage formation and maintenance of the extracellular matrix required for healthy cartilage function.

The extracellular matrix is a network of proteins and other molecules surrounding cells. In cartilage, it provides structure, helps the tissue withstand pressure, and supports the smooth surface needed for joint movement.

Overall, the treatment appeared to move cartilage toward a younger biological state without adding stem or progenitor cells.

Human cartilage samples also respond to treatment

The researchers next examined cartilage removed from people with osteoarthritis during total knee replacement surgery.

After one week of treatment with a 15-PGDH inhibitor, the number of 15-PGDH-producing chondrocytes in the human tissue was reduced. Compared with untreated samples, the treated tissue also showed less activity in genes linked to cartilage breakdown and fibrocartilage formation.

Most notably, the samples began producing new articular cartilage.

“This mechanism is quite surprising and has revolutionized our view of how tissue regeneration occurs,” Bhutani said. “It is clear that the large pool of cells already present in cartilage has altered gene expression patterns, and targeting these cells for regeneration may provide an opportunity for greater overall clinical impact.”

Human clinical trials are still needed

The findings do not yet prove that 15-PGDH inhibition can regenerate cartilage or prevent osteoarthritis in people. Results from mice and experiments using human tissue provide important early evidence, but clinical trials specifically testing cartilage regeneration will be necessary to determine whether the treatment is safe and effective for patients.

Oral 15-PGDH inhibitors have already entered clinical trials for another age-related condition: muscle weakness.

“A phase 1 clinical trial of a 15-PGDH inhibitor for muscle weakness showed it to be safe and effective in healthy volunteers,” Blau said. “Our hope is that similar trials will begin soon to test its effects in cartilage regeneration. We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement.”

Researchers at the Sanford Burnham Prebys Medical Discovery Institute contributed to this study.

This research was supported by the National Institutes of Health (grants R01AR070864, R01AR077530, R01AG069858, and R00NS120278), Baxter Stem Cell Biology Foundation, Li Ka-Shing Foundation, Stanford Heart and Vascular Institute, Milky Way Research Foundation, Canadian Institutes of Health Research, Stanford Translational Research and Applied Medicine Pilot Grant, GlaxoSmithKline Sir James Black Postdoctoral Fellowship, and Stanford University Dean’s Postdoctoral Fellowship.

Blau, Bhutani, and other co-authors are inventors on a Stanford University patent application covering 15-PGDH inhibition for cartilage and tissue rejuvenation. The applications are licensed to Epirium Bio. Blau is a co-founder of Myoforte/Epirium and holds stock and stock options in the company.