BY THE OPTIMIST DAILY EDITORIAL TEAM
A Stanford Medicine study has identified a protein that roughly doubles in aging joints and blocks cartilage from repairing itself. Blocking that protein in older mice regenerated hyaline cartilage across the joint surface. Human tissue samples from knee replacement surgeries responded the same way after just one week of treatment.
The protein, 15-PGDH, is a gerozyme: a class of proteins that accumulate with age and suppress tissue regeneration across the body. It works by degrading prostaglandin E2, a molecule that drives tissue repair. As 15-PGDH rises with age, prostaglandin E2 falls, and regeneration slows across muscle, bone, nerve, and blood. The same team identified gerozymes in 2023. This paper, published in Science, is the first to show the mechanism in cartilage.
How cartilage aging differs from other tissues
Cartilage regeneration does not work the way researchers expected. Most tissue repair runs on stem cells: they multiply, differentiate, and produce new specialized cells. Cartilage appears to skip that entirely.
The cells already in the joint, called chondrocytes, can shift their gene expression and return to a more functional state without any stem cell involvement. “We were looking for stem cells, but they are clearly not involved,” said Helen Blau, PhD, professor of microbiology and immunology and senior author of the study. “It’s very exciting.”
In aging joints, chondrocytes drift toward inflammation and collagen breakdown. As collagen goes, cartilage thins and softens, producing the pain and swelling of osteoarthritis. Elevated 15-PGDH is part of what pushes cells in that direction.
What blocking 15-PGDH did in older mice
Researchers gave older mice a small molecule that blocks 15-PGDH, delivered either by abdominal injection or directly into the knee joint. Both worked. Cartilage that had thinned with age grew thicker, and the new tissue was hyaline cartilage, the smooth, load-bearing type needed for normal joint movement, not fibrocartilage, a lower-quality substitute.
In untreated aging cartilage, chondrocytes responsible for breakdown made up eight percent of cells; after treatment, three percent. Cells associated with fibrocartilage production dropped from 16 to 8 percent. Cells that build hyaline cartilage and maintain the surrounding matrix rose from 22 to 42 percent.
“Cartilage regeneration to such an extent in aged mice took us by surprise,” said Nidhi Bhutani, PhD, associate professor of orthopedic surgery and co-senior author. “The effect was remarkable.”
Protection after ACL-type injury
About half of people who tear their ACL develop osteoarthritis in that joint within 15 years. In the mouse model, untreated ACL-injured animals had 15-PGDH levels roughly twice those of uninjured mice and had osteoarthritis within four weeks. That’s a compressed version of a process that takes over a decade in humans.
Mice given the inhibitor twice weekly for four weeks after injury were far less likely to develop it. They also walked more normally and put more weight on the injured limb.
Human tissue also responded
The most striking result may be the human tissue data. The team tested cartilage from total knee replacement surgeries: end-stage, already-failed joints. After one week of treatment, those samples showed fewer degraded cells, less gene activity tied to breakdown, and new articular cartilage growth.
“It’s clear that a large pool of already existing cells in cartilage are changing their gene expression patterns,” Bhutani said. “And by targeting these cells for regeneration, we may have an opportunity to have a bigger overall impact clinically.”
Toward clinical trials
A Phase 1 trial of a 15-PGDH inhibitor for muscle weakness has already been completed with safety confirmed and biological activity observed in healthy volunteers. A cartilage trial is the next step.
Osteoarthritis affects hundreds of millions of people globally and is a primary driver of joint replacement surgery. No approved drug currently addresses the cartilage loss itself, only the symptoms. “Until now, there has been no drug that directly treats the cause of cartilage loss,” Bhutani said. “But this gerozyme inhibitor causes a dramatic regeneration of cartilage beyond that reported in response to any other drug or intervention.”
Source study: Science— Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration
Did this solution stand out? Share it with a friend or support our mission by becoming an Emissary.
