A study by scientists at The Forsyth Institute has suggested strategies for triggering the body to make new cartilage cells, which could have major implications in regenerative medicine for repairing cartilage injuries and degeneration. In their paper in Science Advances, co-first author Takamitsu Maruyama, PhD, and Daigaku Hasegawa, PhD, together with and senior author Wei Hsu, PhD, and colleagues, described two breakthrough discoveries, including a new understanding of a multifaced protein called β-catenin. Maruyama stated, “The goal of this study was to figure out how to regenerate cartilage. We wanted to determine how to control cell fate, to cause the somatic cell to become cartilage instead of bone.” Their report is titled “GATA3 mediates nonclassical β-catenin signaling in skeletal cell fate determination and ectopic chondrogenesis.”
As any weekend warrior understands, cartilage injuries to joints such as knees, shoulders, and hips can prove extremely painful and debilitating. In addition, conditions that cause cartilage degeneration, like arthritis and temporomandibular joint disorder (TMJ), affect 350 million people in the world and cost the US public health system more than $303 billion every year. Patients suffering from these conditions experience increased pain and discomfort over time.
Previously, it was thought that the Wnt signal transduction pathway was the determinant of whether a cell became bone or cartilage. The master factor transducing the Wnt signals is β-catenin. The basis for this belief was the result that when β-catenin was disrupted, the bone became cartilage. “The importance of Wnt signaling in skeletal lineage commitment has been implicated by the study of β-catenin–deficient mouse models,” the authors explained. “Ectopic chondrogenesis caused by the loss of β-catenin leads to a long-standing belief in canonical Wnt signaling that determines skeletal cell fate.”
However, β-catenin also acts as a cell adhesion molecule to facilitate cell-cell interaction— the original function identified prior to the discovery of its role in Wnt signaling. “We know that this molecule is important for cell fate determination, but the mechanism remained open to study,” said Hsu. The authors continued, “As β-catenin has other functions, it remains unclear whether skeletogenic lineage commitment is solely orchestrated by canonical Wnt signaling.”
The team tested what would happen when β-catenin was only partially impaired for signaling, finding that, in that case, the cells were unable to form bone or cartilage. “we have created several mouse models to examine details of the skeletal cell fate decision mediated by β-catenin,” they explained. Through their experiments, the scientists concluded that Wnt signaling is a determinant for bone formation, but that it isn’t sufficient for cartilage generation. “We wanted to know what the factor was for cell fate determination,” said Maruyama. “What reprograms a cell to become cartilage if it isn’t Wnt signaling?”
This question led to the second major discovery, of the involvement of GATA3 in an alternative action of β-catenin responsible for skeletal cell fate switching. GATA3 is a single gene regulator, which turns on cartilage-specific gene expression in cells. “Gene expression profiling and bioinformatics analyses further identify GATA3 to mediate the nonclassical signaling effect of β-catenin on skeletal cell fate determination,” the authors noted, further concluding “GATA3 alone is sufficient to promote ectopic cartilage formation, demonstrating its essential role in mediating nonclassical β-catenin signaling in skeletogenic lineage specification.” Hsu added, “GATA3 binds to the genome sequences required for the reprogramming. GATA3 is a game changer because we can use it to potentially change any somatic cell to become a cartilage-forming cell, similar to using four stem cell factors to generate embryonic stem cell-like cells called induced pluripotent stem cells (iPSC).”
Being able to control the cell fate in this way may make it possible to direct a cell to become bone, cartilage, or fat, which has tremendous implications for creating new treatments for the one in four people living with cartilage injuries and cartilage degeneration. There is currently no treatment that can regenerate cartilage, and current treatments are unable to improve joint function.
Hsu is a senior scientist at the Forsyth Institute and a Professor of Developmental Biology at Harvard University. He is also an affiliate faculty member of the Harvard Stem Cell Institute. Additional study authors included Swiss scientists Tomas Valenta PhD, and Konrad Basler, PhD, and Canadian scientists Jody Haigh, PhD, and Maxime Bouchard, PhD.