Pharmaceutical Targets Identified For Osteoarthritis
By Deborah Borfitz
February 6, 2024 | Researchers from the University of Adelaide (Australia) and the Columbia University (New York) have “reimagined” osteoarthritis, providing a pharmaceutical target for the discovery of drugs to reverse and treat the ubiquitous degenerative joint disease. Osteoarthritis was originally believed to be a “wear and tear” condition, and some people still refer to it that way, which wrongly implies that its progression is a matter of time and inevitable, according to Jia Ng, now a senior research commercialization associate at AusHealth, a health charity organization supporting medical research in Australia.
As a postdoctoral researcher in the school of medicine at the University of Adelaide, Ng co-led a study showing that a population of stem cells marked by the Gremlin 1 (Grem1) gene is responsible for development of osteoarthritis, as reported recently in Nature Communications (DOI: 10.1038/s41467-023-42199-1). Treatment with fibroblast growth factor 18 (FGF18, known clinically as Sprifermin) stimulated the proliferation of Grem1 cells in the joint cartilage of mice, leading to significant recovery of cartilage thickness and reduced osteoarthritis.
The Grem1 gene is a family of bone morphogenic protein involved in “regulating organogenesis, body patterning, and tissue differentiation,” says Ng. It is also known to have roles in the intestine, bone marrow, pancreas, and brain, as well as skeletogensis (limb bud development) in the early stages of embryonic development. “It was only natural to be curious about its role in skeletal disease such as osteoarthritis.”
The prospect of potentially repairing and regenerating cartilage has implications beyond osteoarthritis to all injury to the articular cartilage—the living tissue lining the bony surface of joints—where the Grem1 stem cells exist, Ng says. “Cartilage has historically been a difficult tissue to regenerate due to the limited blood flow within the tissue that facilitates regeneration. The uniqueness of stem cells is the fact that they have the potential to self-regenerate, therefore, where they exist lies the potential for repair.”
But the “biggest opportunity” uncovered by the latest study is a target for osteoarthritis treatment that has been shown to work, she notes. Other groups have similarly experimented with the concept of stimulating cartilage cells, called chondrocytes, with varying degrees of success. Stem cell therapies designed to stimulate the traditional mesenchymal stem cell population “may not actually be a suitable/effective target,” as suggested in the paper by Ng and her colleagues.
Stem Cell Defects
Being a stem cell biologist, Ng understands that disease progression is often the consequence of a compromised stem cell population (e.g., blood and colorectal cancers), she says. “The question for me was then, why not osteoarthritis? All mature cells develop from a particular discreet source of stem cell population, [so] if we can fix the source of mature cells, we can treat and reverse the impairment of all mature cells and tissues.”
That “epiphany” came from the work of her supervisor, gastroenterologist Daniel Worthley, who founded these cells while looking at their role in the gut and also noticed their presence in the articular cartilage (Cell, DOI: 10.1016/j.cell.2014.11.042). The next obvious question was whether articular cartilage stem cells have a role in disease and what that is, she says. “The leading disease in the articular joint was then obvious—osteoarthritis.”
The disease impacts people over the age of 45, particularly females, she notes. Most treatments concentrate on treating symptoms and improving quality of life, instead of targeting the pathology. This invariably leads to joint replacement surgery, which can have a significant impact on patients’ mental health during the sometimes-lengthy recovery period.
For the past two decades now, the targeting of stem cells through either stimulation or reintroduction has been utilized as a treatment, says Ng. This indicates that the idea of osteoarthritis being a reversible loss of critical articular cartilage stem cells is “not as far-fetched as it seems.”
Many diseases can be attributed, partially or in full, to a defect in the stem cell population, she adds. In his newly released book, “The Song of the Cell: An Exploration of Medicine and the New Human,” study co-senior author Siddhartha Mukherjee, M.D. (assistant professor of medicine at Columbia University Medical Center) describes “the reframing of the human body as a cellular ecosystem [that] leads to the birth of a new kind of medicine based on the therapeutic manipulations of cells,” Ng shares.
Sprifermin Moves Forward
It is believed that a phase 2 clinical trial involving FGF18 is the first to be conducted in the U.S. where a pharmaceutical was utilized to target the articular cartilage tissue for the treatment of osteoarthritis, says Ng, which she and her team were not involved with. Results of the five-year study, published in 2021, found potential long-term clinical benefit and no safety concerns.
Next steps would be to investigate options for bringing pharmaceuticals directly to the targeted Grem1 stem cells for optimal regeneration, which will require further investigation into other unique surface targets of the cells and delivery options, she says.
In Australia, no clinical trials are underway using FGF18 for the treatment of osteoarthritis and it remains an unapproved drug, Ng adds. But it could be reasonably assumed that Australia will follow the lead of the U.S. if Sprifermin gets approved by the Food and Drug Administration. Phase 3 of the Sprifermin trial is ongoing.
“There is still an enormous amount of work to be done in the space of reversing the progression of osteoarthritis to reduce the economic burden and quality of life for patients with osteoarthritis,” says Ng. But Grem1-expressing articular cartilage progenitor cells, and the signaling pathway that sustains them and is activated by FGF18, appear to be effective targets for biological management of the disease.