Mouse Study Regrows Knee Cartilage by Blocking Aging Protein

What did the Stanford-led team test?

Researchers focused on a protein called 15-PGDH, an enzyme whose levels roughly doubled with age in mouse knee cartilage¹². The team tested a small-molecule inhibitor that blocks this enzyme, first in older mice and then in mice with a knee injury similar to an ACL tear¹². The question was whether reducing 15-PGDH could restore cartilage and reduce osteoarthritis in these models¹².

In osteoarthritis, the joint's cartilage wears away over time, leaving the area painful, swollen and harder to move¹. The condition is estimated to affect about one in five adults in the United States¹. Current treatments mainly manage pain and other symptoms, and severe cases may require joint replacement; no approved drug reliably slows or reverses the disease itself¹.

Cartilage in the body is not all the same¹. Elastic cartilage is soft and flexible, while fibrocartilage is tougher and better at absorbing force¹. The smooth, slippery tissue that allows bones to glide over one another is hyaline cartilage, also called articular cartilage, which is the type most commonly damaged by osteoarthritis¹.

How did blocking 15-PGDH change cartilage cells?

Rather than using stem cells, the treatment prompted existing chondrocytes to alter which genes were active and take on a more youthful profile¹².

In the single-cell analysis, one group of older chondrocytes that made 15-PGDH and showed gene activity for cartilage breakdown fell from 8% to 3%¹². A second group that lacked 15-PGDH and expressed fibrocartilage-related genes declined from 16% to 8%¹. Meanwhile, a third group that lacked 15-PGDH and expressed genes for forming hyaline cartilage increased from 22% to 42%¹.

The extracellular matrix consists of proteins and other molecules that surround cells and provide structural support¹. Within cartilage, this matrix matters because it lets the tissue handle pressure and keeps the joint surface smooth for movement¹.

What did the mouse experiments show?

After treatment, knee cartilage in older mice became thicker and consisted of the smooth articular cartilage that joints need to move without friction¹². In the injury model, mice treated twice a week for four weeks after an ACL-type injury were less likely to develop osteoarthritis and put more weight on the injured leg than animals that did not receive the inhibitor¹.

The published abstract reports that both systemic and local inhibition of 15-PGDH regenerated articular cartilage and reduced osteoarthritis-associated pain in mice². By about 15 years after an ACL tear, roughly 50% of people have developed osteoarthritis in that joint¹. Mice that received a control drug showed 15-PGDH levels twice as high as those of uninjured mice and developed osteoarthritis within four weeks¹.

Researchers observed that cartilage regeneration to this extent in aged mice was surprising¹. The treated mice also moved more normally than untreated animals¹.

What happened in human cartilage?

The group also tested cartilage removed from people with osteoarthritis during operations to replace the entire knee¹. After one week of exposure to the inhibitor, treated samples contained fewer cells making 15-PGDH, and genes related to cartilage breakdown and fibrocartilage were also less active than in untreated tissue¹.

The important observation was that the samples started to form new articular cartilage¹. Even so, these results do not yet show that the approach regrows cartilage or prevents osteoarthritis in humans; researchers say clinical studies are required¹. An oral 15-PGDH inhibitor has already reached early clinical testing for muscle weakness, and researchers hope a similar trial will be launched soon for cartilage regeneration¹.

Frequently asked questions