15-PGDH Inhibitor May Restore Cartilage in Mice

15-PGDH inhibitor restores cartilage in mice

Researchers at Stanford University have linked age-related cartilage loss in mice to a single protein, raising the prospect of treatments that could eventually improve mobility and relieve discomfort in older people.

The protein, 15-PGDH, has long been strongly associated with ageing. Its levels rise as we age, disrupting molecules responsible for tissue repair and reducing inflammation.

This prompted the team to investigate whether 15-PGDH plays a role in osteoarthritis, a condition in which strain on the joints breaks down cartilage collagen and results in inflammation and pain.

Cartilage regeneration and protection from osteoarthritis

In older mice, knee cartilage that had already deteriorated became thicker after a 15-PGDH inhibitor was introduced. Comparable experiments in young mice with injuries found that the inhibitor protected them from the typical consequences of injury-induced osteoarthritis.

The researchers created the mouse equivalent of an anterior cruciate ligament injury, then administered the treatment. Osteoarthritis failed to develop, despite normally being expected in this type of mouse model.

Earlier cartilage-regeneration approaches had involved stem cells. However, blocking 15-PGDH removed the need for them. Instead, chondrocytes - the cells that produce and maintain cartilage - shifted into a healthier, more functional state.

"This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to aging or injury," says microbiologist Helen Blau. "We were looking for stem cells, but they are clearly not involved. It's very exciting."

Mice receiving the treatment walked with a more consistent gait, indicating that they were likely in less pain. They also placed more weight on their injured legs, suggesting that cartilage restoration had improved their physical condition.

Human cartilage samples show similar changes

The team also carried out the experiment using human tissue samples collected from people undergoing knee-replacement surgery. Once again, the results showed clear evidence of regeneration: the cartilage became stiffer and displayed fewer signs of inflammation.

"The mechanism is quite striking and really shifted our perspective about how tissue regeneration can occur," says orthopaedic scientist Nidhi Bhutani. "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."

Although substantial work remains, the findings could ultimately produce treatments that reverse damage caused by arthritis or ageing more broadly. They may point towards a future in which hip and knee replacements are unnecessary.

Current osteoarthritis treatments, apart from replacing affected joints, are limited to pain relief. Despite encouraging research in recent years, no available therapy yet addresses the underlying cause of the condition.

Clinical trial prospects

A clinical trial could be among the next stages. An earlier trial of a 15-PGDH blocker for muscle weakness raised no health or safety concerns, potentially accelerating trials of similar medicines.

"We are very excited about this potential breakthrough," says Blau. "Imagine regrowing existing cartilage and avoiding joint replacement."

The research was published in Science.