New Method May Restore Cartilage in Aging Joints

Researchers have discovered a method that appears to restore cartilage in aging knee joints, at least in mice, by inhibiting a specific protein whose levels increase with age. This technique not only reversed the natural decline of cartilage in older mice but also shielded them from developing arthritis following knee injuries akin to ACL tears seen in humans.

Interestingly, the results showed potential applicability to human tissue as well. Samples of cartilage taken during knee replacement surgeries responded favorably to the treatment, initiating the production of new, functional cartilage.

The combined findings hint that cartilage affected by aging or arthritis could be more amenable to repair than previously assumed. If this strategy proves effective for humans, researchers speculate it might lead to a medication or injection capable of regenerating cartilage, possibly reducing the necessity for knee or hip replacement surgeries.

Addressing the Core Issues of Osteoarthritis

Osteoarthritis is a degenerative condition affecting joints, where cartilage deteriorates over time, resulting in pain, swelling, and reduced mobility. About one in five adults in the U.S. suffers from this condition, leading to approximately $65 billion in direct healthcare costs yearly.

Current treatment options primarily target pain and symptoms. If the disease becomes severe, surgical joint replacement may become the only viable solution. At present, there is no medication that reliably slows or reverses the progression of osteoarthritis.

This study, led by Stanford Medicine, focused on a protein known as 15-PGDH. Researchers have labeled it a “gerozyme,” which refers to enzymes that increase with age and contribute to the gradual decline of tissue function.

Previous research from the same team indicated that 15-PGDH plays a crucial regulatory role in aging within various tissues. When they blocked the protein in aged mice using a small molecule, it resulted in increased muscle mass and endurance. Conversely, boosting 15-PGDH levels in younger mice led to muscle atrophy and weakness. The protein has also been linked to regenerating bone, nerve, and blood cells.

Unlike many tissues that rely on stem cells for healing, cartilage showcases a different trend. Instead of depending on stem cells, the existing cartilage cells, called chondrocytes, altered their gene activity patterns and reverted toward a more youthful state.

“This represents a novel approach to regenerating adult tissue and holds considerable promise for treating arthritis resulting from aging or injuries,” stated Helen Blau, PhD, a professor of microbiology and immunology. “Our initial focus was on stem cells, but they aren’t involved as we expected. It’s quite thrilling.”

Blau, along with Nidhi Bhutani, PhD, an associate professor of orthopedic surgery, served as senior authors of the study, which was published in Science. Other notable contributors include Mamta Singla, PhD, an instructor in orthopedic surgery, and Yu Xin (Will) Wang, PhD, a former postdoctoral scholar, who now holds a faculty position at the Sanford Burnham Institute in San Diego.

Significant Cartilage Regeneration Observed

“Millions of individuals endure joint pain and swelling as they age,” Bhutani noted. “It really is a significant unmet medical need. Up until now, no medication has directly addressed the underlying cause of cartilage depletion. Yet, this gerozyme inhibitor leads to a substantial regeneration of cartilage, exceeding what other drugs or interventions have achieved.”

Human cartilage consists of three primary types, each serving distinct functions. Elastic cartilage is soft and flexible, aiding structures like the outer ear. Fibrocartilage is tougher and designed for absorbing stress, appearing between spinal vertebrae. In contrast, hyaline cartilage is smooth and permits minimal friction between bones in joints, such as the knees and hips, being the type most commonly affected by osteoarthritis.

Osteoarthritis often emerges as joints endure stress due to aging, injuries, or excess weight, leading chondrocytes to produce inflammatory molecules while simultaneously breaking down collagen—an essential structural protein for cartilage strength. This loss of collagen causes cartilage to thin and soften, leading to inflammation and pain, typical symptoms of osteoarthritis.

The challenge lies in the fact that articular cartilage has limited ability to heal. Although researchers have identified potential stem or progenitor cells that could generate cartilage in bone, finding similar populations within articular cartilage has proven elusive.

The Targeting of an Aging Protein

Earlier findings from Blau’s lab had revealed that prostaglandin E2 plays a critical role in muscle stem cells’ functions. The protein 15-PGDH is responsible for breaking down prostaglandin E2. Blocking 15-PGDH or raising prostaglandin E2 levels has promoted regeneration in damaged muscle, nerve, and other cells in young mice.

This led the researchers to ponder: Could this biological mechanism also contribute to cartilage deterioration as animals grow older or recover from injuries?

The team compared levels of 15-PGDH in knee cartilage from both young and aged mice, finding that the protein’s quantity essentially doubled with age. They then administered a small molecule drug aimed at inhibiting 15-PGDH in older animals, using both abdominal injections for systemic effect and direct deliveries into the knee joint.

Both treatment methods yielded remarkable results. The cartilage in the knees of older mice, which initially appeared noticeably thinner and less functional than that of younger mice, became thicker after treatment.

Crucially, these cells generated hyaline cartilage—the smooth articular cartilage necessary for healthy joint movement—rather than the less suitable fibrocartilage.

“We were genuinely surprised by the extent of cartilage regeneration in aged mice,” Bhutani remarked. “The effects were quite extraordinary.”

Protecting Knees Post-ACL Injuries

The team also explored whether the treatment could aid recovery after traumatic knee injuries. ACL tears are prevalent in sports like soccer and basketball, where athletes make quick pivots and stops. Surgery can repair the torn ligament, but it doesn’t always prevent long-lasting joint damage.

About half of those suffering from these injuries develop osteoarthritis in the affected joint within roughly 15 years. In their experiments, the researchers administered the gerozyme inhibitor twice weekly for four weeks following injury. This treatment significantly lessened the likelihood that the mice would develop osteoarthritis.

Conversely, mice receiving a control drug showed 15-PGDH levels twice those of uninjured mice and developed osteoarthritis within a month. Treated mice exhibited more typical movement patterns and bore more weight on the injured leg compared to untreated counterparts.

“Interestingly, prostaglandin E2 is often associated with inflammation and pain,” Blau noted. “However, our research indicates that, at normal biological levels, small boosts in prostaglandin E2 can actually encourage regeneration.”

Fostering a Younger State in Old Cartilage Cells

To delve into the internal mechanisms at play, the researchers investigated chondrocytes from both young and old mice. They found that older cartilage cells displayed heightened activity in genes tied to inflammation and the unwanted transformation of hyaline cartilage into bone, while genes related to normal cartilage development showed diminished activity.

Treatment shifted this balance positively. The proportion of older chondrocytes that produced 15-PGDH and expressed genes associated with cartilage degradation dropped from 8% to 3%. Another group with no 15-PGDH production but linked to fibrocartilage formation declined from 16% to 8%. Conversely, a third group, which did not produce 15-PGDH but expressed genes for forming hyaline cartilage and maintaining the extracellular matrix, surged from 22% to 42%.

The extracellular matrix represents the network of proteins and other molecules surrounding cells, providing structure to tissues. In cartilage, it’s particularly vital as it helps the tissue endure pressure while preserving the smooth surfaces required for joint movement.

Overall, the treatment appeared to encourage the cartilage to adopt a more youthful biological state without involving stem or progenitor cells.

Responses from Human Cartilage

The researchers further examined cartilage from individuals with osteoarthritis undergoing total knee replacement surgery. After a week’s treatment with the 15-PGDH inhibitor, the human tissue exhibited fewer chondrocytes producing 15-PGDH. There was also a decline in gene activity linked to cartilage degradation and fibrocartilage compared to untreated samples.

Significantly, the human samples began regenerating articular cartilage.

“The mechanism is truly striking and has shifted our understanding of how tissue regeneration may occur,” Bhutani stated. “It’s evident that a substantial pool of pre-existing cells in the cartilage is altering their gene expression. By targeting these cells for regeneration, we might have an opportunity for a more substantial clinical impact.”

While the findings do not definitively confirm that this treatment can regrow cartilage or prevent osteoarthritis in humans, the positive results in mice and human tissue provide essential early evidence. However, specific clinical trials will be necessary to assess the safety and effectiveness of this approach in patients.

There’s already an oral 15-PGDH inhibitor in clinical testing for a different age-related issue: muscle weakness. Blau expressed hope, “Phase 1 trials of a 15-PGDH inhibitor for muscle weakness have demonstrated safety and efficacy in healthy volunteers. We are optimistic a similar trial might soon be initiated to evaluate its effectiveness in regenerating cartilage. This potential breakthrough could really change the landscape—imagine regrowing existing cartilage and avoiding joint replacements.”