Stanford University study links 15-PGDH to ageing cartilage loss in osteoarthritis

Researchers at Stanford University have used a mouse study to pin the age-related decline of cartilage on a single protein, a finding that could eventually support treatments aimed at improving mobility and easing discomfort in older people.

The protein, known as 15-PGDH, has long been associated with ageing. Levels of it rise over time, and it disrupts molecules involved in tissue repair and in calming inflammation.

Linking 15-PGDH to osteoarthritis and cartilage breakdown

Because osteoarthritis develops when repeated stress on joints contributes to collagen breakdown within cartilage-bringing inflammation and pain in its wake-the team investigated whether 15-PGDH might be part of that process.

Mouse experiments with a 15-PGDH inhibitor

In older mice, knee cartilage that had already become worn showed thickening after the animals were given a 15-PGDH inhibitor. In separate experiments using younger mice with joint injuries, the same inhibitor helped shield cartilage from the typical progression seen in injury-driven osteoarthritis.

The researchers also induced the equivalent of an anterior cruciate ligament injury in mice and then followed up with the treatment. In this model, osteoarthritis failed to develop, despite the fact that it normally would in comparable mouse studies.

Earlier efforts to regenerate cartilage had included the use of stem cells; in these experiments, that approach was no longer required when 15-PGDH was blocked. Rather than relying on stem cells, the chondrocytes that create and sustain cartilage appeared to shift 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."

Following treatment, mice walked with a more consistent gait-an indicator of reduced pain-and they were observed placing more weight on the previously injured leg. Together, these changes suggested that the cartilage recovery was linked to improved physical function.

Human tissue results and the road to clinical trials

The team ran the same type of experiment on human tissue samples taken from people undergoing knee replacement surgery. Here too, regeneration signals were evident: cartilage became stiffer and displayed fewer markers 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 contribute to treatments that reverse damage caused by arthritis or ageing more broadly. In time, that might reduce the need for hip and knee replacements.

At present, osteoarthritis care-aside from joint replacement-offers relatively few options beyond managing pain. Even with encouraging research in recent years, there is still no established therapy that addresses the underlying cause of the disease.

A logical next move would be a clinical trial. Notably, an earlier trial of a 15-PGDH blocker for muscle weakness did not raise major concerns around health and safety, which could help accelerate trials of related drugs.

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

The research has been published in Science.