Stanford scientists regrow lost cartilage and reverse arthritis in major breakthrough
Stanford Medicine
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| Miraculous healing |
A treatment that targets a protein linked to aging has
restored lost knee cartilage in older mice and prevented arthritis from
developing after serious joint injuries, according to a Stanford Medicine-led
study.
Researchers also found encouraging results in human tissue.
Samples collected during knee replacement surgeries began producing new,
functional cartilage when exposed to the treatment.
The findings raise the possibility that damaged cartilage
caused by aging or osteoarthritis could one day be repaired with either a local
injection or an oral medication. If successful in people, the approach could
reduce the need for knee and hip replacement surgeries.
An oral version of the treatment is already being tested in
clinical trials for age-related muscle weakness.
Targeting the Root Cause of Osteoarthritis
Osteoarthritis is the most common form of arthritis and
affects about one in five adults in the United States. The disease gradually
breaks down cartilage in the joints, causing pain, stiffness, and swelling. It
is estimated to generate roughly $65 billion in direct health care costs each
year.
Current treatments focus mainly on pain relief and, in
severe cases, joint replacement surgery. No approved medication can slow, stop,
or reverse the underlying disease process.
The new treatment works by blocking a protein called
15-PGDH, which researchers describe as a "gerozyme." This class of
proteins becomes more abundant with age and contributes to declining tissue
function throughout the body.
The same research team first identified gerozymes in 2023.
Previous studies showed that 15-PGDH plays a major role in age-related muscle
decline in mice. When researchers block the protein, older animals gain muscle
mass and endurance. When the protein is artificially increased in young mice,
their muscles become weaker and smaller.
Scientists have also linked 15-PGDH to the regeneration of
bone, nerve, and blood cells.
A Different Type of Tissue Regeneration
In many tissues, regeneration occurs because stem cells
multiply and develop into new specialized cells. Cartilage appears to work
differently.
Instead of relying on stem cells, cartilage-producing cells
called chondrocytes seem able to shift their gene activity and return to a more
youthful state.
"This is a new way of regenerating adult tissue, and it
has significant clinical promise for treating arthritis due to aging or
injury," said Helen Blau, PhD, professor of microbiology and immunology.
"We were looking for stem cells, but they are clearly not involved. It's
very exciting."
Blau, director of the Baxter Laboratory for Stem Cell
Biology and the Donald E. and Delia B. Baxter Foundation Professor, and Nidhi
Bhutani, PhD, associate professor of orthopedic surgery, are the senior authors
of the study, which was published in Science. Instructor of
orthopedic surgery Mamta Singla, PhD, and former postdoctoral scholar Yu Xin
(Will) Wang, PhD, are the lead authors. Wang is now an assistant professor at
the Sanford Burnham Institute in San Diego.
Remarkable Cartilage Regrowth
"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."
The human body contains three main forms of cartilage.
Elastic cartilage provides flexibility in structures such as the outer ear.
Fibrocartilage is tough and shock-absorbing, found in places like the discs
between vertebrae. Hyaline cartilage is smooth and slippery, allowing joints
such as the knees, hips, shoulders, and ankles to move freely.
Osteoarthritis primarily damages hyaline cartilage, also
called articular cartilage.
As joints age or experience injury or excess stress from
obesity, chondrocytes begin producing inflammatory molecules and breaking down
collagen, the main structural component of cartilage. As collagen disappears,
cartilage becomes thinner and softer. Inflammation then triggers the pain and
swelling associated with osteoarthritis.
Unlike many other tissues, articular cartilage rarely
repairs itself. While researchers have identified possible cartilage-producing
stem cells in bone, similar cells have not been successfully identified in
articular cartilage.
Why Researchers Focused on 15-PGDH
Earlier work from Blau's laboratory showed that
prostaglandin E2 is critical for muscle stem cell function. The protein 15-PGDH
breaks down prostaglandin E2.
When researchers inhibit 15-PGDH or increase prostaglandin
E2 levels, damaged muscle, nerve, bone, colon, liver, and blood tissues
regenerate more effectively in young mice.
The team wondered whether the same mechanism might influence
cartilage aging.
When they compared cartilage from young and old mice, they
found that levels of 15-PGDH approximately doubled with age.
To test the idea, researchers treated older mice with a
small molecule drug that blocks 15-PGDH activity. Some animals received
injections into the abdomen, exposing the whole body to the treatment. Others
received injections directly into the knee joint.
Both approaches produced striking results. Cartilage that
had become thinner and less functional with age grew thicker across the joint
surface. Additional testing showed the regenerated tissue was hyaline
cartilage, the type needed for healthy joint function, rather than the less
effective fibrocartilage.
"Cartilage regeneration to such an extent in aged mice
took us by surprise," Bhutani said. "The effect was remarkable."
Preventing Arthritis After ACL-Type Injuries
The researchers also investigated whether the treatment
could protect joints after injury.
They used a mouse model that mimics ACL tears, a common
sports injury seen in activities such as soccer, basketball, and skiing that
involve sudden stopping, pivoting, or jumping.
Although ACL injuries can be surgically repaired, roughly
half of affected people develop osteoarthritis in the injured joint within
about 15 years.
Mice that received the gerozyme inhibitor twice weekly for
four weeks after injury were far less likely to develop osteoarthritis. In
contrast, untreated animals showed 15-PGDH levels that were about twice as high
as those of uninjured mice and developed osteoarthritis within four weeks.
Treated mice also walked more normally and placed more
weight on the injured limb.
"Interestingly, prostaglandin E2 has been implicated in
inflammation and pain," Blau said. "But this research shows that, at
normal biological levels, small increases in prostaglandin E2 can promote
regeneration."
Reprogramming Aging Cartilage Cells
A closer look at cartilage cells revealed important
differences between young and old joints.
Older chondrocytes were more likely to activate genes linked
to inflammation and unwanted conversion of cartilage into bone. They were less
likely to express genes associated with healthy cartilage formation.
The treatment appeared to reverse many of these age-related
changes.
One group of chondrocytes that produced 15-PGDH and
expressed genes involved in cartilage breakdown dropped from 8% of cells to 3%
after treatment. Another group associated with fibrocartilage production fell
from 16% to 8%.
Meanwhile, a population of cells involved in building
hyaline cartilage and maintaining the extracellular matrix increased from 22%
to 42%.
Overall, the results suggest the treatment shifts cartilage
toward a younger, healthier state without requiring stem or progenitor cells.
Human Cartilage Also Responded
The team then examined cartilage removed from people
undergoing total knee replacement surgery for osteoarthritis.
After one week of treatment with the 15-PGDH inhibitor, the
tissue showed fewer cartilage-degrading cells and lower activity of genes
linked to cartilage breakdown and fibrocartilage production. The samples also
began generating new articular cartilage.
"The mechanism is quite striking and really shifted our
perspective about how tissue regeneration can occur," Bhutani said.
"It's clear that a large pool of already existing cells in cartilage are
changing their gene expression patterns. And by targeting these cells for
regeneration, we may have an opportunity to have a bigger overall impact
clinically."
Blau added, "Phase 1 clinical trials of a 15-PGDH
inhibitor for muscle weakness have shown that it is safe and active in healthy
volunteers. Our hope is that a similar trial will be launched soon to test its
effect in cartilage regeneration. We are very excited about this potential
breakthrough. Imagine regrowing existing cartilage and avoiding joint
replacement."
Researchers from the Sanford Burnham Prebys Medical
Discovery Institute also contributed to the study.
The research was funded by the National Institutes of
Health (grants R01AR070864, R01AR077530, R01AG069858 and R00NS120278), the
Baxter Foundation for Stem Cell Biology, the Li Ka Shing Foundation, the
Stanford Cardiovascular Institute, the Milky Way Research Foundation, the
Canadian Institutes of Health Research, a Stanford Translational Research and
Applied Medicine Pilot grant, a GlaxoSmithKline Sir James Black Postdoctoral
Fellowship, and a Stanford Dean's Postdoctoral Fellowship.
Blau, Bhutani, and several co-authors are inventors on
Stanford University patent applications involving 15-PGDH inhibition for
cartilage repair and tissue rejuvenation that have been licensed to Epirium
Bio. Blau is a co-founder of Myoforte/Epirium and holds equity and stock
options in the company.
Journal Reference:
- Mamta
Singla, Yu Xin Wang, Elena Monti, Yudhishtar Bedi, Pranay Agarwal, Shiqi
Su, Sara Ancel, Maiko Hermsmeier, Nitya Devisetti, Akshay Pandey, Mohsen
Afshar Bakooshli, Adelaida R. Palla, Stuart Goodman, Helen M. Blau, Nidhi
Bhutani. Inhibition of 15-hydroxy prostaglandin dehydrogenase
promotes cartilage regeneration. Science, 2026; 391
(6789): 1053 DOI: 10.1126/science.adx6649
