Blocking an ageing protein could help damaged knee cartilage regrow

The conventional wisdom surrounding damaged joint cartilage is not particularly encouraging. Once the smooth, resilient tissue coating the ends of bones deteriorates, its capacity to repair itself is extremely limited. New research indicates this assumption may need revisiting.

Scientists led by Stanford Medicine have identified a molecular intervention that produced substantial cartilage regeneration in ageing mice. The approach also protected animals against osteoarthritis following knee injuries and, significantly, stimulated cartilage taken from people undergoing knee replacement surgery to produce new articular cartilage.

The research centres on inhibiting an enzyme called 15-hydroxyprostaglandin dehydrogenase, or 15-PGDH. Its abundance increases as animals age, making it what the researchers term a “gerozyme”, an enzyme associated with age-related deterioration in tissue function. The implications could be considerable. Rather than replacing an extensively damaged joint, future treatments might conceivably encourage cartilage already within it to regenerate. That prospect, however, remains some distance from clinical reality. The evidence so far comes from animals and laboratory experiments with human tissue rather than clinical trials demonstrating cartilage regeneration in patients.

Going after cartilage loss itself

Osteoarthritis develops as the protective cartilage within a joint progressively deteriorates. This can lead to pain, stiffness, swelling and declining mobility. It is also a substantial public health problem. There is consequently considerable interest in therapies capable of modifying the underlying disease rather than concentrating primarily on symptomatic relief or replacing a severely damaged joint. This latest approach is unusual because it targets biological ageing.

The Stanford researchers had previously discovered that 15-PGDH has an important influence over the function of ageing tissues. The enzyme degrades prostaglandin E2 (PGE2), a signalling molecule implicated in tissue regeneration. Earlier work found that inhibiting 15-PGDH increased muscle mass and strength in old mice, while raising levels of the enzyme in young animals had the opposite effect. The pathway has additionally been associated with regenerative responses in tissues including bone, nerves and blood.

Cartilage presented the researchers with a different biological problem. Many forms of tissue repair depend upon stem cells dividing before developing into specialised replacement cells. Articular cartilage, the smooth hyaline cartilage covering joint surfaces, has very poor intrinsic repair capacity, and attempts to identify an equivalent regenerative population within this tissue have proved difficult. Yet regeneration still occurred when 15-PGDH was suppressed.

Comparing knee cartilage from young and old mice revealed that levels of 15-PGDH approximately doubled with age. The scientists then treated older mice with a small-molecule inhibitor of the enzyme. They tested both systemic administration and delivery directly into the knee. Age-thinned cartilage grew thicker following treatment. Importantly, this was hyaline cartilage, the smooth material needed at joint surfaces, rather than fibrocartilage, a tougher form of cartilage with different mechanical properties.

According to senior author Helen Blau, professor of microbiology and immunology at Stanford University: “This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to aging or injury.” She added: “We were looking for stem cells, but they are clearly not involved. It’s very exciting.”

Instead, the answer appears to reside with chondrocytes, the cells already present within cartilage. Analysis of their gene activity suggested inhibition of 15-PGDH caused populations of ageing chondrocytes to change state. Cells displaying patterns associated with cartilage deterioration and fibrocartilage declined, while the proportion expressing genes connected with healthy hyaline cartilage and its supporting extracellular matrix increased.

In other words, the treatment did not appear to provide cartilage with a fresh supply of replacement stem cells. It persuaded substantial numbers of its existing cells to adopt a more regenerative, youthful programme. This potentially represents a different way of thinking about tissue regeneration: working with mature cells already present rather than depending upon a reservoir of stem cells to replace them.

Could it protect an injured knee?

The potential application is not restricted to age-related deterioration. Knee trauma is an important risk factor for subsequent osteoarthritis, and anterior cruciate ligament (ACL) injuries can leave people vulnerable to degenerative joint disease long after the original ligament has been repaired. The researchers therefore simulated ACL-like injuries in mice and administered the 15-PGDH inhibitor twice weekly for four weeks.

Animals receiving the treatment were substantially protected against the development of osteoarthritis. Their movement and willingness to put weight through the injured leg also improved compared with untreated animals. The result points towards another possible therapeutic strategy: intervening after an injury to alter the later biological trajectory of the joint. This would be fundamentally different from repairing the immediate structural injury while waiting to see whether osteoarthritis subsequently develops.

There is an intriguing complexity surrounding prostaglandin E2 as well. The molecule is associated with inflammatory processes and pain, yet the research suggests that modest increases within normal biological ranges can also contribute to regeneration. As Blau observed: “Interestingly, prostaglandin E2 has been implicated in inflammation and pain. But this research shows that, at normal biological levels, small increases in prostaglandin E2 can promote regeneration.”

Perhaps the most consequential part of the research involved cartilage that did not come from mice at all. The scientists obtained cartilage from people with osteoarthritis undergoing total knee replacement operations. When this tissue was exposed to the 15-PGDH inhibitor for a week, fewer chondrocytes expressed the enzyme, while gene activity associated with degradation and fibrocartilage declined. Of great interest was the finding that the human samples began regenerating articular cartilage.

This does not demonstrate that administering the drug to a person will rebuild their knee. Tissue studied outside the human body cannot reproduce all the biological, mechanical, pharmacological and safety factors encountered in a living patient. It does, however, strengthen the biological argument for investigating the pathway clinically because human osteoarthritic cartilage retained a capacity to respond.

“The mechanism is quite striking and really shifted our perspective about how tissue regeneration can occur,” senior author Nidhi Bhutani, associate professor of orthopaedic surgery, said. According to Bhutani, the work indicates that a large population of cells already present in cartilage is capable of changing its pattern of gene expression. Targeting these existing cells could therefore potentially provide a route towards regeneration without having to supply replacement cells.

From replacement to regeneration?

Regenerative medicine is increasingly exploring alternative ways to address skeletal and cartilage damage. Other researchers, for example, are investigating tissue engineering approaches, including cell-free cartilage scaffolds designed to encourage the body to regenerate damaged bone. The 15-PGDH strategy is different. Rather than supplying a replacement scaffold, it attempts to reactivate regenerative behaviour within cells that are already present.

This is also where expectations require careful management. No evidence from the study establishes that people can yet take a 15-PGDH inhibitor and regrow an arthritic knee or hip. Clinical trials specifically designed to assess joint treatment will be necessary to determine appropriate dosing and safety and, crucially, whether the striking regeneration observed experimentally translates into meaningful improvements for patients.

If mature cartilage cells are not irreversibly trapped in an ageing, degenerative condition, cartilage loss may prove more biologically reversible than previously assumed. A future medicine might therefore seek not merely to suppress pain while degeneration continues, but to persuade the joint itself to rebuild some of what ageing or injury has taken away.