Sci Tech Daily investigates a new treatment for arthritis that can not just stop joint damage but actually reverse it by blocking chemicals associated with aging … even in young patients:
Researchers at Stanford Medicine report that blocking a protein linked to aging can restore cartilage that naturally wears away in the knees of older mice. In the study, the injectable treatment not only rebuilt cartilage but also stopped arthritis from developing after knee injuries similar to ACL tears, which are common among athletes and active adults. A pill-based version of the same therapy is already being tested in clinical trials aimed at treating muscle weakness associated with aging.
Human knee tissue collected during joint replacement surgeries also responded positively to the treatment. These samples, which include both the joint’s supporting extracellular scaffolding, or matrix, and cartilage-producing chondrocyte cells, began forming new cartilage that functioned normally.
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The therapy targets a protein called 15-PGDH, which becomes more abundant as the body ages and is classified as a gerozyme. Gerozymes, first described by the same research team in 2023, play a central role in aging by contributing to the gradual decline of tissue function. In mice, rising levels of 15-PGDH are a key factor in the loss of muscle strength that occurs with age. When scientists block this protein using a small molecule, older mice show gains in muscle mass and endurance. In contrast, forcing young mice to produce 15-PGDH causes their muscles to weaken and shrink. The protein has also been linked to the regeneration of bone, nerve, and blood cells.
In those tissues, repair depends on the activation and specialization of tissue-specific stem cells. Cartilage behaves differently. Instead of relying on stem cells, chondrocytes alter their gene activity in ways that restore a more youthful state, allowing regeneration to occur without stem cell involvement.
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Previous research from Blau’s lab has shown that a molecule called prostaglandin E2 is essential to muscle stem cell function. 15-PGDH degrades prostaglandin E2. Inhibiting 15-PGDH activity, or increasing levels of prostaglandin E2, supports the regeneration of damaged muscle, nerve, bone, colon, liver and blood cells in young mice.
Blau, Bhutani and their colleagues wondered if 15-PGDH might also play a role in aging cartilage and joints. They wanted to find out if a similar pathway contributes to cartilage loss from aging or in response to injury. When they compared the amount of 15-PGDH in the knee cartilage in young versus old mice, they saw that, as in other tissues, levels of the gerozyme increased about two-fold with age.
They next experimented with injecting old animals with a small molecule drug that inhibits 15-PGDH activity — first into the abdomen, which affects the entire body, then directly into the joint. In each case, the knee cartilage, which was markedly thinner and less functional in older animals as compared with younger mice, thickened across the joint surface. Further experiments confirmed that the chondrocytes in the joint were generating hyaline, or articular, cartilage, rather than less-functional fibrocartilage.
“Cartilage regeneration to such an extent in aged mice took us by surprise,” Bhutani said. “The effect was remarkable.”
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Similar results were observed in animals with knee injuries like the ACL tears that frequently occur in people participating in sports such as soccer, basketball and skiing that require sudden pivoting, stopping or jumping. While the tears can be surgically repaired, about 50% of people develop osteoarthritis in the injured joint within about 15 years.