Inhibiting a master regulator of aging regenerates joint cartilage in mice

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The knee joint of a young mouse (top), aged mouse (middle) and treated aged mouse (bottom). The red indicates cartilage. Nidhi Bhutani

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Aging & Geriatrics November 27, 2025

Inhibiting a master regulator of aging regenerates joint cartilage in mice

By Krista Conger

Osteoarthritis due to aging or injury affects 20% of the U.S. population. A Stanford Medicine-led study found that blocking a ‘gerozyme’ reverses cartilage loss in mice and human tissue.

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An injection that blocks the activity of a protein involved in aging reverses naturally occurring cartilage loss in the knee joints of old mice, a Stanford Medicine-led study has found. The treatment also prevented the development of arthritis after knee injuries mirroring the ACL tears often experienced by athletes or recreational exercisers. An oral version of the treatment is already in clinical trials with the goal of treating age-related muscle weakness.<br>\nSamples of human tissue from knee replacement surgeries — which include both the extracellular scaffolding, or matrix, in the joint as well as cartilage-generating chondrocyte cells — also responded to the treatment by making new, functional cartilage.<br>\nThe study results suggest it may be possible to regenerate cartilage lost to aging or arthritis with an oral drug or local injection, rendering knee and hip replacement unnecessary.<br>\nThe treatment directly targets the cause of osteoarthritis, a degenerative joint disease that affects one of every five adults in the United States and is estimated to cost about $65 billion in direct health care costs each year. No drug can slow down or reverse the disease; the primary treatments for osteoarthritis are pain control and surgical replacement of the affected joints.<br>\nThe protein, 15-PGDH — termed a gerozyme due to its increase in prevalence as the body ages — is a master regulator of aging. Gerozymes, identified by the same researchers in 2023, also drive the loss of tissue function. They are a major force behind age-related loss of muscle strength in mice. Blocking the function of 15-PGDH with a small molecule results in an increase in old animals’ muscle mass and endurance. Conversely, expressing15-PGDH in young mice causes their muscles to shrink and weaken. The gerozyme has also been implicated in the regeneration of bone, nerve and blood cells.<br>\nIn each of these tissues, regeneration is due to increases in the proliferation and specialization of tissue-specific stem cells. However, chondrocytes change their patterns of gene expression to assume a more youthful state without the involvement of stem cells.&nbsp;<br>\n“This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to aging or injury,” said&nbsp;Helen Blau, PhD, professor of microbiology and immunology. “We were looking for stem cells, but they are clearly not involved. It’s very exciting.”<br>\nBlau, who directs the&nbsp;Baxter Laboratory for Stem Cell Biology and is the Donald E. and Delia B. Baxter Foundation Professor, and Nidhi Bhutani, PhD, associate professor of orthopaedic surgery, are the senior authors of the research, which was published online Nov. 27 in Science. Instructor of orthopaedic surgery Mamta Singla, PhD, and former postdoctoral scholar Yu Xin (Will) Wang, PhD, are the lead authors of the study. Wang is now an assistant professor at the Sanford Burnham Institute in San Diego.&nbsp;<br>\n‘Dramatic regeneration’<br>\n“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.”<br>\nThere are three main types of cartilage in the human body. One, elastic cartilage, is soft and flexible and forms structures like the outer ear. A second, fibrocartilage, is dense and tough, absorbing shock in areas such as between the spinal vertebrae. The third, hyaline cartilage, is smooth and glossy, providing a low-friction surface for lubrication and flexibility in joints like the ankles, hips, shoulders and parts of the knee. Hyaline cartilage — also known as articular cartilage — is the cartilage most commonly affected by osteoarthritis.<br>\nOsteoarthritis occurs when a joint is stressed by aging, injury or obesity. The chondrocytes begin to release pro-inflammatory molecules and to break down collagen, which is the primary structural protein of cartilage. When collagen is lost, the cartilage thins and softens; the accompanying inflammation...