Jan 06, 2026
3 min read
The treatment has also prevented the development of arthritis after knee injuries, such as ACL tears that are common in athletes.
A study by Stanford Medicine found that an injection that blocks the activity of a protein involved in aging restores cartilage loss that occurs naturally in the knee joints of old mice.
Treatment also prevents the development of arthritis after a knee injury, such as an ACL tear that occurs in athletes or recreational players.Oral therapy is already in clinical trials with the goal of treating age-related muscle weakness.
Human tissue samples from knee replacement surgeries responded to the treatment by producing new functional cartilage, suggesting that knee and hip replacements may not be necessary in the future.
The treatment targets the direct cause of osteoarthritis, a common joint disease that affects one in five adults in the United States and is estimated to cost nearly $65 billion in direct health care costs each year.Prevention or substitution is the only strategy for society, as no drug can slow or reverse the disease.
The protein blocked by the injection, 15-PGDH, is a key regulator of aging and is actually called a "gerozyme" because its abundance increases with age.Gerozymes also cause tissue destruction.They are the main force behind the age-related loss of muscle strength in mice.
Blocking the action of 15-pgdh with a small molecule increased muscle mass and endurance in older animals.In contrast, expressing 15-pgdh in young mice caused their muscles to contract and weaken.
In bone, nerve and blood cells, regeneration occurs due to increased proliferation and specialization of tissue-specific stem cells.However, the chondrocytes that produce cartilage change their gene expression pattern to adopt a more youthful state without the involvement of stem cells.
"This is a new way to regenerate tissue in adults and has significant clinical promise for treating arthritis caused by aging or trauma," said Helen Blah, Ph.D., professor of microbiology and immunology.
Nidhi Bhutani, PhD and associate professor of orthopedic surgery, said, "Millions of people suffer from joint pain and swelling as they age," said Blau's colleague and co-author.
There are three main types of cartilage in the human body.One, hyaline cartilage, is smooth and shiny, providing a low friction surface for lubrication and flexibility in joints such as the ankle, hip, shoulder, and knee.Hyaline cartilage—also called articular cartilage—is the cartilage most commonly affected by osteoarthritis.
Osteoarthritis occurs when the joint is affected by old age, injury or obesity.Chondrocytes begin to release pro-inflammatory substances and break down collagen, which is the main protein of cartilage.When collagen is lost, the cartilage becomes soft and flabby;the inflammation associated with it causes joint inflammation and pain which are symptoms of the disease.Under normal conditions, articular cartilage rarely regenerates.cells that can form cartilage in bone, attempts to find such a number of cells in cartilage have not been successful.
Previous research from Blau's lab showed that a molecule called prostaglandin E2 is essential for muscle stem cell function.15-PGDH cleaves prostaglandin E2.Inhibiting 15-PGDH activity, or increasing prostaglandin E2 levels, promotes regeneration of damaged muscle, nerve, bone, colon, liver and blood cells in young mice.
Blau, Bhutan and their colleagues wondered if 15-PGDH might also play a role in the aging of cartilage and joints.They wanted to know if the same process contributes to the loss of cartilage from aging or in response to injury.When they compared the amount of 15-PGDH in the knee cartilage of young and old mice, they found that, like other tissues, the levels of gerozyme increased approximately twofold with age.
Next, they experimented with injecting older animals with a small-molecule drug that blocks the action of 15-PGDH, first in the abdomen, which affects the whole body, and then directly in the joint.In each case, knee cartilage, which was thinner and less functional in older animals than in younger mice, was thickened at the joint surface.Further experiments confirmed that chondrocytes in the joint form hyaline or articular cartilage instead of nonfunctional fibrocartilage.
“Cartilage regeneration in old mice took us by surprise,” Bhutani said."The effect was amazing."
Similar results have been seen in animals with knee injuries, such as ACL tears, which often occur in people who participate in sports such as football, basketball and skiing that require sudden turning, stopping or jumping.Although tears can be repaired surgically, about 50 percent of people develop osteoarthritis in the damaged joint within about 15 years.
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Researchers found that injections of a gerozyme inhibitor twice a week for four weeks after injury significantly reduced the chance of osteoarthritis developing in the mice.Animals treated with jerozyme inhibitors also moved more normally.and caused more weight on the paws of the affected legs than in untreated animals.
"Interestingly, prostaglandin E2 has been implicated in inflammation and pain," Bello said.
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A close study of chondrocytes in the joints of old mice and young mice showed that old chondrocytes expressed more harmful genes related to inflammation and the conversion of hyaline cartilage to unwanted bone, and less genes involved in cartilage development.
Researchers studied human cartilage tissue from osteoarthritis patients who had undergone total knee replacement.Tissue treated with a 15-PGDH inhibitor for one week showed lower levels of 15-PGDH-expressing chondrocytes and reduced cartilage degradation and fibrocartilage genes than control tissue, and initiated articular cartilage regeneration.
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"The mechanism is fascinating and has changed our view of how cell regeneration can be done," Bhutan said."It is clear that many of the cells already present in the cartilage are changing their gene expression patterns. And by targeting these cells for regeneration, we may have the opportunity to have a greater clinical impact."
"Phase 1 clinical trials of a 15-PGDH inhibitor for muscle weakness have shown that it is safe and active in healthy volunteers," Blau said."Our hope is that a similar study will soon be launched to test its effect on cartilage regeneration. We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement."
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