Blocking a master regulator of aging regenerates joint cartilage in mice

Good news!

"In brief

• A Stanford Medicine-led study shows blocking the protein 15-PGDH reverses cartilage loss in aging mice and human tissue.
• The treatment could replace traditional osteoarthritis management, offering a novel approach to joint regeneration without stem cells.
• Researchers highlight clinical potential, aiming to initiate trials for cartilage regeneration, addressing a significant unmet medical need.

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. ...

The 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, expressing 15-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. ..."

From the abstract:

"Aging or injury to the joints can lead to cartilage degeneration and osteoarthritis (OA), for which there are limited effective treatments.

We found that expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) is increased in the articular cartilage of aged or injured mice.

Both systemic and local inhibition of 15-PGDH with a small molecule inhibitor (PGDHi) led to regeneration of articular cartilage and reduction in OA-associated pain.

Using single cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage, we identified the major chondrocyte subpopulations.

Inhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and increased extracellular matrix-synthesizing articular chondrocytes. Cartilage regeneration appears to occur through gene expression changes in pre-existing chondrocytes, rather than stem or progenitor cell proliferation. 15-PGDH inhibition could be a potential disease-modifying and regenerative approach for osteoarthritis."

Blocking a master regulator of aging regenerates joint cartilage in mice | Stanford Report "A new study suggests 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."

Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration (no public access)

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