Scientists at Stanford have discovered a method to regenerate knee cartilage in aged mice and human tissue samples by focusing on a protein whose production increases with age. The research, detailed in Science, opens the door to a medication that might address arthritis without requiring joint replacement surgery.
Researchers stopped a protein known as 15-PGDH, which grows in quantity as creatures grow older. When given to aged rodents, the intervention brought back cartilage that had vanished over time. The treatment likewise shielded animals from becoming arthritic following knee injuries that resemble ACL tears in humans. Cartilage taken from human knees during joint replacements started making fresh, working joint material when treated with the same inhibitor.
The Protein That Ages Cartilage
A degenerative condition affecting the joints, osteoarthritis causes cartilage to wear away over time, leaving people with painful, swollen joints that grow harder to move. In the United States, it touches roughly one in five grown-ups, and it is estimated to cost the country about $65 billion in direct health care expenses annually.
Managing pain and other symptoms remains the primary approach to treating the condition today. When the disease advances significantly, surgical replacement of the damaged joint often becomes the sole remaining choice. No medication has yet proven capable of slowing or reversing osteoarthritis itself.
The Stanford Medicine-led study centered on 15-PGDH, which the researchers classify as a gerozyme — a label for enzymes whose abundance increases with age and which help bring about the gradual decline in tissue function.
Earlier research from the same team found that 15-PGDH functions as a key controller of aging across several body parts. When the protein was blocked using a small chemical, older mice gained more muscle mass and showed improved endurance. In contrast, raising 15-PGDH levels in youthful creatures led to their muscles growing smaller and losing strength. This protein has additionally been tied to the renewal of bone, nerve, and blood cells.
Cartilage Regeneration Without Stem Cells
Tissue-specific stem cells multiply and develop into specialized cells in many body parts during recovery. However, cartilage works in a distinct way.
Instead of relying on stem cells, existing cartilage cells called chondrocytes changed their patterns of gene activity and shifted toward 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 Helen Blau, PhD, professor of microbiology and immunology.
“We were looking for stem cells, but they are clearly not involved. It’s very exciting.”
The Baxter Laboratory for Stem Cell Biology is led by Blau, who serves as its director. The other senior author is Nidhi Bhutani, PhD, who holds the title of associate professor of orthopaedic surgery. The lead authors of the study are Mamta Singla, PhD, an instructor of orthopedic surgery, and Yu Xin (Will) Wang, PhD, a former postdoctoral scholar. Wang has since moved on to become an assistant professor at the Sanford Burnham Institute in San Diego.
How 15-PGDH Affects Cartilage
Levels of prostaglandin E2 can be raised by blocking 15-PGDH, a move that has been shown to support the repair of damaged muscle, nerve and other body parts. In cartilage, the result is particularly striking.
The human cartilage samples showed a particularly striking response. “Millions of people suffer from joint pain and swelling as they age,” Bhutani said. “It is a huge unmet medical need. 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.”
The Three Kinds of Cartilage
There are three principal kinds of cartilage, and each serves its own distinct purpose.
Soft and bendable elastic cartilage assists in shaping the outer ear, while firmer fibrocartilage handles force absorption, such as between the spinal vertebrae. Hyaline cartilage is smooth and slippery, letting bones slide past one another with almost no friction in joints like the ankles, hips, shoulders and certain parts of the knee.
Osteoarthritis most often damages a particular kind of cartilage found in joints. That type of cartilage is called articular cartilage, which is another name for hyaline cartilage.
Why Articular Cartilage Is Hard to Fix
The joint damage seen in osteoarthritis stems from years of wear, injury or excess weight. As this strain builds up, chondrocytes start releasing inflammatory substances even as they break apart the very collagen that keeps cartilage strong.
The cartilage grows thinner and more delicate as its collagen vanishes. Swelling and pain follow from inflammation, giving rise to the well-known signs of osteoarthritis.
Articular cartilage does not generally repair itself well. Scientists have found possible stem or progenitor cells capable of producing cartilage inside bone, but attempts to discover similar cell populations directly within articular cartilage have failed.
A Path Toward a Drug
Instead of cultivating fresh cartilage from stem cells, the Stanford researchers are altering how the cells that are already present behave. This is a focused method rather than a broad one.
The difference between those two paths is significant. Regenerative medicine has typically depended on stem cells to reconstruct broken tissue. Here, though, the approach takes a different course, showing instead that cells already present can be guided back to a more youthful and healthy condition — an outcome that matches how the researchers themselves describe their own achievement.
Scientists are working on a pill or shot that could rebuild cartilage and cut down on knee or hip replacement operations. Whether their idea will pan out in human testing is still unknown.
What Comes Next
This research holds promise, yet it remains confined to animal studies and early human data. The gap between a lab dish and an actual patient is significant, and numerous therapies that show success in mice ultimately do not carry over.
The core process remains a clear point of attack. Should 15-PGDH suppression prove safe and reliable in people, the route is already there.
For years, researchers have pursued a cure for osteoarthritis. Now one approach appears distinct from what came before it.
| Mice | Human Samples | |
|---|---|---|
| Treatment | Block 15-PGDH | Block 15-PGDH |
| Outcome | Restored lost cartilage | New, functional cartilage production |
| Context | Aging animals | Knee replacement patients |
Scientists say aged or arthritic cartilage may hold more promise for repair than earlier research indicated. They propose a method that might eventually yield an oral medicine or injection capable of regenerating cartilage, thereby reducing the need for knee or hip replacement surgery.
Millions of people who endure joint pain see real hope in a drug that targets the cause rather than the symptom. The journey from the lab to clinical use is lengthy, yet the results so far are encouraging, though still at an early stage.
Source material: “Goodbye joint replacements? Stanford scientists found a way to regrow cartilage and stop arthritis,” ScienceDaily.
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