Researchers at Stanford Medicine have published a study identifying a treatment that, in mice, reversed age-related knee cartilage loss and prevented arthritis development following injury. The treatment involves blocking a protein known as 15-PGDH. Human cartilage samples from knee replacement surgeries also responded positively to the treatment.
Key Findings
The study found that levels of the protein 15-PGDH increase with age. In elderly mice, blocking this protein led to a measured thickening of knee cartilage that had previously deteriorated. In young mice, a course of the inhibitor administered after an induced knee injury prevented the development of osteoarthritis.
"The research represents a new way of regenerating adult tissue, with significant clinical promise for treating arthritis due to aging or injury." — Dr. Helen Blau, Stanford Medicine
Researchers stated that the observed cartilage regeneration did not occur through stem cell activation. Instead, chondrocytes (cartilage-producing cells) were observed to change their gene expression patterns to a more youthful, functional state.
Study Details
- Protein Target: The treatment inhibits the protein 15-PGDH, which researchers have previously referred to as a "gerozyme"—a term used to describe proteins whose levels increase with age and contribute to tissue dysfunction.
- Comparison: An analysis of knee cartilage from young and old mice showed a doubling of 15-PGDH levels in the older animals.
- Administration: The inhibitor was administered to older mice either systemically or via direct injection into the knee joint, resulting in thicker cartilage across the joint surface. Tests indicated the regenerated tissue was hyaline cartilage.
- Injury Prevention: Mice that received twice-weekly injections of the inhibitor for four weeks following an ACL-like injury were less likely to develop osteoarthritis. The treated mice demonstrated improved mobility and weight-bearing on the injured leg.
- Cellular Mechanism: Analysis of chondrocytes in treated mice showed a shift in gene expression away from inflammation and cartilage-to-bone conversion, and toward hyaline cartilage formation. Researchers noted this effect did not involve stem cells.
"It's clear that a large pool of already existing cells in cartilage are changing their gene expression patterns." — Dr. Nidhi Bhutani, Stanford Medicine
Human Tissue Response
Human cartilage tissue samples obtained from patients undergoing total knee replacement surgeries were treated with the 15-PGDH inhibitor for one week. The tissue showed a reduction in 15-PGDH-producing chondrocytes, decreased expression of degradation and fibrocartilage genes, and displayed early signs of articular cartilage regeneration.
Broader Context
Osteoarthritis is a degenerative joint disease affecting approximately one in five U.S. adults, with direct healthcare costs estimated at $65 billion annually. Current treatments primarily manage pain or involve surgical joint replacement, as no approved drugs are known to slow or reverse cartilage damage.
A separate research group at the University of Colorado Boulder has reported a slow-release drug-delivery system injected into damaged joints that repaired cartilage and bone in animals.
Future Steps
A Phase 1 clinical trial of a 15-PGDH inhibitor for age-related muscle weakness has demonstrated safety and activity in healthy volunteers. Researchers expressed hope to initiate a similar trial to investigate its effects on cartilage regeneration.
Dr. Blau, Dr. Bhutani, and co-authors hold patent applications related to 15-PGDH inhibition in cartilage and tissue rejuvenation, which have been licensed to Epirium Bio. Dr. Blau is a co-founder of Myoforte/Epirium and holds equity in the company.