Cartilage injuries to joints such as the knees, shoulders, and hips can be extremely painful and debilitating. In addition, conditions that cause cartilage degeneration, such as arthritis and temporomandibular joint (TMJ) disorder, affect 350 million people worldwide. Patients suffering from these conditions experience increased pain and discomfort over time.
Now, a Forsyth Institute study suggests new strategies for manufacturing cartilage cells with huge regenerative medicine implications for future treatments of cartilage injury and degeneration.
In a paper published in Science Advances, co-authors Takamitsu Maruyama and Daigaku Hasegawa, and lead author Wei Hsu, describe two groundbreaking discoveries, including a new understanding of a multifaceted protein called β-catenin.
“The aim of this study -says Maruyama- was to find out how to regenerate cartilage. We wanted to determine how to control the fate of the cells, to make the somatic cell become cartilage instead of bone.”
Until now, it was thought that the Wnt signal transduction pathway was what determined whether a cell became bone or cartilage. The master factor that transduces Wnt signals is β-catenin. The basis for this belief was the result that when β-catenin was disrupted, bone turned into cartilage.
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 signalling. “We know that this molecule is important in determining cell fate, but the mechanism was left open for study,” Hsu says.
The team tested what would happen when β-catenin was only partially prevented from signaling, finding that, in that case, the cells were unable to form bone or cartilage. After these tests, the scientists concluded that Wnt signaling is determinant for bone formation, but that it is not enough for the generation of cartilage.
“We wanted to know what was the factor that determined the fate of the cells,” says Maruyama. “What reprograms a cell to become cartilage if not Wnt signaling?”
This question led to a second major discovery: GATA 3, an alternative action of β-catenin responsible for the fate change of skeletal cells. GATA3 is a unique gene regulator that activates cartilage-specific gene expression in cells. “Basically,” Wei Hsu said, “GATA3 binds to the genome sequences required for 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 cells similar to embryonic stem cells called pluripotent stem cells. induced (iPSC)”.
Being able to control the fate of cells in this way directs a cell to become bone, cartilage, or fat, which has huge implications for creating new treatments for the 1 in 4 people living with cartilage injury and degeneration. Currently there is no treatment that can regenerate cartilage, and current treatments are unable to improve joint function.