Drug target regrows knee cartilage in mice and human tissue

Scientists have found a way to regrow worn-out knee cartilage in mice by blocking a protein that builds up with age, raising hopes of a future treatment that could reduce the need for knee and hip replacements.

The study, led by Stanford Medicine and published in the journal Science, found that the approach reversed natural cartilage loss in older mice and protected younger mice from developing arthritis after knee injuries similar to a torn anterior cruciate ligament in people.

Encouragingly, the treatment also worked on human tissue. Cartilage removed during knee replacement operations began producing new, functional cartilage when it was treated in the laboratory.

The protein behind the problem

The researchers targeted a protein called 15-PGDH, which they describe as a "gerozyme": an enzyme that becomes more abundant with age and contributes to the gradual loss of tissue function.

15-PGDH breaks down a molecule called prostaglandin E2, which helps tissues repair themselves. The same team had previously shown that blocking 15-PGDH increased muscle mass and endurance in old mice, and the protein has been linked to the regeneration of bone, nerves and blood cells.

A surprise in the cartilage

In many tissues, healing depends on stem cells multiplying and turning into specialised cells. But cartilage behaved differently. Instead of stem cells, the existing cartilage cells, called chondrocytes, changed which of their genes were active and shifted back towards 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," said Professor Helen Blau, one of the senior authors. "We were looking for stem cells, but they are clearly not involved. It's very exciting."

Her fellow senior author, Associate Professor Nidhi Bhutani, said: "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."

Why cartilage matters

The smooth, slippery cartilage that lines joints such as the knees, hips and shoulders lets bones glide over each other with very little friction. In osteoarthritis, the cartilage cells begin producing inflammatory molecules and breaking down collagen, the protein that gives cartilage its strength. The cartilage becomes thinner and softer, leading to pain, swelling and stiffness.

Articular cartilage normally has very little ability to repair itself, which is why current treatments focus mainly on managing pain. Once the disease becomes severe, replacing the joint is often the only option.

What comes next

The results so far come from mice and from human tissue in the laboratory, and treatments that work in animals often do not work in people. Clinical trials would be needed to show whether blocking 15-PGDH is safe and effective in patients.

If it does work, the researchers believe it could lead to a tablet or an injection that regenerates cartilage. That would be a significant change for the millions of people in the UK living with osteoarthritis, which is one of the leading causes of pain and disability, and for the NHS, which carries out more than 100,000 knee and hip replacements every year.