Stem cell discovery raises prospect of reversing osteoarthritis

Researchers have found that osteoarthritis in mice is caused by the depletion of specialized gene-expressing cartilage-forming stem cells and found a way to reverse the condition. The discovery opens the door to treating the painful condition instead of just managing its symptoms.

Osteoarthritis (OA) affects all joint tissues, and leads to the loss of articular cartilage, whose principal function is to provide a smooth, lubricated surface that allows bones to move smoothly past each other.

There’s no cure for the long-term, progressive condition. Rather, the symptoms of joint pain and stiffness are managed with analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), the long-term use of which has actually been associated with hastened progression of osteoarthritis symptoms. But, in a new study, researchers at the University of Adelaide in South Australia have found that OA may be not only treatable, but it may be reversible.

“The findings of our study reimagine osteoarthritis not as a ‘wear and tear’ condition but as an active and pharmaceutically reversible loss of critical articular cartilage stem cells,” said Jia Ng, lead author of the study.

Articular cartilage is a permanent tissue that requires the support of self-renewing progenitor cells – descendants of stem cells – to repopulate chondrocytes, the cells responsible for forming cartilage. However, the regenerative capacity of articular cartilage is limited, with OA often resulting from injury, chronic mechanical stress or increasing age – so-called ‘wear and tear.’

Focusing on the knee joint of adult mice, the researchers found that a specialized population of chondrogenic progenitor cells resides on the articular surface and generates articular cartilage. These cells, marked by the Gremlin 1 gene, were depleted in OA. They showed, through their experiments, that loss of Gremlin-1-expressing chondrogenic progenitor cells is an early event in OA and, in turn, also causes OA.

To discover molecular targets in Gremlin 1 cells for OA treatments, the researchers focused on fibroblast growth factor signaling, given the role this pathway has in regulating cartilage development or chondrogenesis. Treating the mice with fibroblast growth factor 18 (FGF18), which has previously been shown to stimulate the production of a number of tissues in the animals, caused the proliferation of Gremlin 1 cells in joint cartilage, leading to significant recovery of cartilage thickness and reduced OA.

“With this new information, we are now able to explore pharmaceutical options to directly target the stem cell population that is responsible for the development of articular cartilage and progression of osteoarthritis,” Ng said. “Our study suggests that there may be new ways to treat the disease rather than just the symptoms, leading to better health outcomes and quality of life for people who suffer from osteoarthritis.”

The discovery also presents opportunities for cartilage regeneration in other forms of injury and disease.

It remains to be seen if the findings will translate from mice to human subjects, but the results of a five-year clinical trial using FGF18, known clinically as Sprifermin, to treat knee OA were published in 2021. While Sprifermin did not alleviate OA symptoms, the study found it was safe and may result in an improvement in cartilage thickness and volume. Phase 3 trials are ongoing.

The study was published in the journal Nature Communications.

Source: University of Adelaide

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