Aging joints may not be as one-way as they seem.

A Stanford Medicine-led study found that blocking a protein linked to aging restored lost knee cartilage in older mice and helped prevent osteoarthritis after serious joint injuries. Human cartilage samples taken during knee replacement surgeries also began producing new, functional cartilage when exposed to the treatment.

The study was published in Science.

Researchers said the treatment targets a protein called 15-PGDH, which they describe as a “gerozyme.” They found levels of 15-PGDH roughly doubled with age in mouse cartilage.

To test the approach, the team treated older mice with a small molecule drug that blocks 15-PGDH activity. Some mice received injections into the abdomen and others got injections directly into the knee joint.

Both methods led to thicker cartilage across the joint surface. Tests showed the new tissue was hyaline cartilage, the smooth cartilage needed for healthy joint function, rather than fibrocartilage.

“Cartilage regeneration to such an extent in aged mice took us by surprise,” said Nidhi Bhutani, PhD, associate professor of orthopedic surgery at Stanford. “The effect was remarkable.”

The researchers also tested the treatment in a mouse model that mimics ACL tears. Mice treated with the gerozyme inhibitor twice a week for four weeks after injury were far less likely to develop osteoarthritis. Untreated mice had 15-PGDH levels about twice as high as uninjured mice and developed osteoarthritis within four weeks.

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

“Interestingly, prostaglandin E2 has been implicated in inflammation and pain,” said Helen Blau, PhD, professor of microbiology and immunology at Stanford. “But this research shows that, at normal biological levels, small increases in prostaglandin E2 can promote regeneration.”

The team found cartilage appears to regenerate differently from many other tissues. Instead of relying on stem cells, cartilage-producing cells called chondrocytes seemed 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,” Blau said. “We were looking for stem cells, but they are clearly not involved. It’s very exciting.”

In older cartilage, chondrocytes were more likely to switch on genes linked to inflammation and the conversion of cartilage into bone, and less likely to express genes tied to healthy cartilage formation. After treatment, one group of chondrocytes involved in cartilage breakdown fell from 8 percent of cells to 3 percent. Another group associated with fibrocartilage production dropped from 16 percent to 8 percent. A group involved in building hyaline cartilage and maintaining the extracellular matrix rose from 22 percent to 42 percent.

The team also tested 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, lower activity in genes linked to cartilage breakdown and fibrocartilage production, and the start of new articular cartilage growth.

“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.”

Osteoarthritis is the most common form of arthritis and affects about one in five adults in the United States, according to the study summary. Researchers said it generates roughly $65 billion in direct health care costs each year. Current treatments mainly focus on pain relief and, in severe cases, joint replacement surgery. No approved medication can slow, stop, or reverse the underlying disease process.

An oral version of the treatment is already being tested in clinical trials for age-related 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. We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement.”

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