Discovery Of New Cells May Help Reverse Osteoarthritis

(Posted on Monday, December 18, 2023)

This article is part of a broad series on recent advances in the science and medicine of longevity and aging. The series covers a range of topics, including musculoskeletal health. Expect more articles on bone and muscle regeneration to follow.

Osteoarthritis has long been considered a “wear-and-tear” disease — with repeated movement and a lifetime of activity, the cartilage and other connective tissues in our joints begin to erode. Unsurprisingly, age is a primary risk factor for osteoarthritis. The problem? The exact cause of the disease is unknown, meaning all currently available treatments are a bandage on a broken leg; they only help to manage symptoms but fail to reverse the loss of cartilage. A new study by researchers at the University of Adelaide, Australia, may help change this. Their work, published in Nature Communications, offers insight into the root causes of osteoarthritis, opening up novel avenues for treatment, and possibly reversal, of the disease. 

Osteoarthritis, Age, and … Stem Cells?

In 2019, half a billion people across the globe were living with osteoarthritis — a 113% increase from 1990. It primarily affects the elderly, with 10% of people over the age of 60 suffering from the condition, often forcing significant lifestyle changes and a decrease in physical activity. The inability to move freely can restrict people’s ability to engage and participate in meaningful activities, leading to psychological stress and discontent. Osteoarthritis is frequently accompanied by severe pain, and stiffening of the affected joints is not uncommon. One in 10 patients will eventually require joint-replacement surgery, an invasive and costly procedure. Even so, for now, it is the best long-term treatment option.

While it is understood that osteoarthritis is a result of cartilage loss, which leaves the bones underneath unprotected and exposed to mechanical stress, it is unclear why cartilage is lost in the first. The “wear-and-tear” explanation suggests that it is simply a result of accumulated strain over years of joint use. In a sense, it’s a repetitive-movement injury. But on a biological level, something must be driving the loss of cartilage. 

With this as a guiding thread, Jia Q. Ng and colleagues managed to unearth a previously unknown subset of progenitor cells defined by the presence of a gene called Gremlin 1 (grem1). These cells were significantly reduced in mice suffering from osteoarthritis compared to their healthy counterparts. The progenitor cells “sit” on the articular surfaces of joints —where the bones meet— and develop into cartilage and bone to help fortify the joints as needed. Crucially, the researchers discovered that the progenitor cells are depleted through joint injury and with age. 

Recovering Lost Cartilage: A Cure?

The importance of the grem1 progenitor cells to joint health was confirmed through mouse models: genetic removal of the cells quickly led to the development of osteoarthritis. And in normal mice suffering from osteoarthritis, the progenitor cells were lost during the earliest stages of disease onset. Combined, the experiments clearly implicate loss of grem1 progenitor cells as a key biological factor in disease onset and progression.

The researchers next sought to leverage this newfound knowledge toward the development of a treatment option. They made use of a protein called fibroblast growth factor 18 (FGF18), which is part of a larger family of proteins intimately involved in cell survival, proliferation, migration, differentiation, and tissue repair. In mice treated with the protein, there was a noticeable uptick in the number of grem1 progenitor cells present in joint cartilage; not only had their loss been curbed, it had been reversed. This uptick in progenitor cells was accompanied by significant recovery of the joints, including improved cartilage thickness and reduced osteoarthritis. Although these are only early results, they provide hope that fibroblast growth factor receptor 3 (FGFR3) signaling —which fibroblast growth factor 18 makes use of— may help treat, and possibly prevent, osteoarthritis. 

In 2021, findings from a five-year clinical trial were released regarding the use of fibroblast growth factor 18, also known as Sprifermin. The study revealed promising long-term clinical advantages and raised no safety concerns. The drug is currently being tested in a phase III clinical trial. Whereas phases I and II of a trial test specifically for efficacy and safety, phase III tests a drug’s performance against the leading available treatment option. It is the last stage of testing before a drug can be approved for use on the market. 

Takeaways

This study has uncovered a cellular basis for osteoarthritis, forcing us to rethink the mechanical wear-and-tear paradigm. The newly discovered Gremlin 1 progenitor cells, which reside on the surface of the joints, play a key role in the development and maintenance of cartilage and bone. Both injury and age are accompanied by a serious decrease in the progenitor cells, which sets the scene for the onset of osteoarthritis. Boosting the number of grem1 progenitor cells using fibroblast growth factor 18 may help treat and reverse the disease.

This article was originally published on Forbes and can be read online here.