Scientists at Stanford Medicine have identified a drug therapy that regenerates damaged joint cartilage in mice and stimulates repair in human tissue, according to research published in the journal Science. The approach could eventually offer an alternative to surgical joint replacement for millions of people living with osteoarthritis.
Osteoarthritis is a degenerative condition in which articular cartilage, the smooth layer cushioning the ends of bones, gradually deteriorates. The disease impacts roughly one in five adults across the United States and generates about $65 billion each year in direct medical expenses, Science Daily reported. Because articular cartilage lacks a blood supply, it possesses virtually no innate capacity to heal once injured or worn away by aging.
Targeting an aging enzyme
The Stanford team focused on 15-PGDH, an enzyme described by researchers as a gerozyme because its abundance increases as tissues grow older. The protein breaks down prostaglandin E2, a molecule essential for tissue repair and cellular recovery. When scientists measured the gerozyme in knee joints, they discovered that older mice had roughly double the levels found in younger animals.
To counteract that loss, investigators administered a small-molecule inhibitor designed to block 15-PGDH, giving it either as a whole-body injection or directly into the knee joint. Both delivery methods caused the animals to develop thicker layers of hyaline cartilage, the resilient, slippery cartilage required for smooth movement in hips, shoulders and knees.
“Until now, there has been no drug that directly treats the cause of cartilage loss,” senior author Nidhi Bhutani, an associate professor of orthopaedic surgery at Stanford, said in remarks reported by Science Daily. Bhutani noted that the drug “causes a dramatic regeneration of cartilage beyond that reported in response to any other drug or intervention.”
Reprogramming existing joint cells
While tissue renewal in muscles and bones typically relies on stem cells multiplying into specialized cells, cartilage reacted differently. Researchers found that existing mature cartilage cells, known as chondrocytes, altered their genetic activity and transitioned into a biologically younger state.
“We were looking for stem cells, but they are clearly not involved,” senior author Helen Blau, a professor of microbiology and immunology, said in a press statement. “This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to aging or injury.”
The researchers also tested the therapy on mice subjected to knee trauma resembling an anterior cruciate ligament tear. About half of humans who endure such injuries eventually develop osteoarthritis, according to the researchers. Mice receiving the inhibitor twice weekly for four weeks showed a markedly reduced rate of arthritis compared with untreated mice, while also walking more normally on the injured limb.
Lab tests yielded similar responses in human tissue. Investigators exposed damaged cartilage harvested from patients undergoing total knee replacement surgery to the inhibitor for one week. The human cells dialed down genetic markers linked to cartilage breakdown and began generating new articular cartilage.
What comes next
While the findings offer a novel framework for joint treatment, the therapy remains unproven in living human patients. Mouse models and isolated tissue specimens do not guarantee identical outcomes during clinical care.
However, an oral version of a 15-PGDH inhibitor has already passed Phase 1 safety trials in healthy human volunteers for age-related muscle weakness, researchers noted. Blau stated that scientists hope to launch clinical trials in the near future to evaluate whether the drug can safely stimulate cartilage regeneration and curb the need for joint replacement surgeries in patients.
