Nearly a quarter of the U.S. population has some form of arthritis, most frequently osteoarthritis—a type of degenerative joint disease that wears down cartilage at the ends of bones, making it painful and difficult to move. Prevalence increases with age, and despite being so common, there’s no cure.
Now, scientists have figured out how a protein contributes to osteoarthritis by controlling the genetic processes involved in cartilage cell aging. In a study published Jan. 13 in Aging Cell, a team led by researchers from the University of Southern California described how they found that suppressing the protein STAT3 worsened osteoarthritis in mouse models. In contrast, activating it reversed the aging process in the cells.
“STAT3 performs an astonishing repertoire of roles in development and regeneration, as well as inflammatory disease and cancer,” co-corresponding author Denis Evseenko, M.D., Ph.D., said in a press release. “In this study, we found an innovative chemical approach for reversing aging of joint-forming cells in a clinically relevant manner, because this intervention is simply and fully controlled.”
STAT3 is present throughout the body and is involved in many diverse processes including cell growth and death, regulation of the immune system and the building and breaking down of bone tissue. Its role in osteoarthritis has been widely explored, albeit with mixed results; while studies have shown that it promotes inflammation, it also promotes tissue regeneration.
The new study from Evseenko’s team suggests that how the protein acts in a cell depends on the cell’s age. When the researchers performed a series of experiments on human cartilage cells from donors, they found there was less STAT3 in young cells than in older ones. They also saw that using a compound to promote STAT3 expression in the cells made their genes biologically younger and caused them to grow more readily while inhibiting the protein aged them.
Homing in on an enzyme involved in cartilage development, DNMT3B, helped explain why. Inhibiting STAT3 raised levels of DNMT3B, which aged the cells’ DNA. In contrast, expressing STAT3 decreased levels of DNMT3B, and, in turn, reduced the age of the genes. And in cartilage cells with osteoarthritis, the absence of STAT3 and increased expression of DNMT3B worsened the condition in mice.
The researchers also noticed something else: STAT3 levels were elevated both in fetal cells and in older cartilage cells with osteoarthritis, compared with healthy adult cells. This suggested that in the context of osteoarthritis, the cells were reverting back to a younger state to regenerate. They found this to be true in mouse models of osteoarthritis too, where cartilage cells appeared to be more immature than those of their healthy counterparts.
But osteoarthritis gets worse over time—not better. Why was it that STAT3-driven tissue regeneration didn’t seem to work as well in cells with osteoarthritis? Inflammation is the likely culprit, according to the researchers. While baseline activation of the STAT3 pathway is important for cartilage development and healing from acute injury, chronic activation as seen in osteoarthritis may lead to the formation of dysfunctional, immature cells, something that was shown in a study back in 2009.
And what about DNMT3B? It will take more studies to understand its role in the process, the researchers said. Future work should focus on therapeutic interventions that balance raising levels of STAT3 with preventing chronic activation of the STAT3 pathway and driving inflammation, the researchers wrote. They also plan to undertake experiments with cartilage cells from a larger group of human donors, which will strengthen their findings.