GRB2 in skin’s blood vessels may have potential as SSc therapy

Reducing GRB2 protein also reduces fibrosis in endothelial cells, study finds

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An illustration of a mouse in a person's hand, which is placed near vials of serum in a lab.

A protein called GRB2 is found in higher levels in cells lining the skin’s blood vessels of people with systemic sclerosis (SSc) than in those of healthy individuals, meaning that GRB2 could be a potential target to treat the disease, a study suggests.

Researchers observed that salvianolic acid B, a plant-derived small molecule, eased fibrosis (scarring) and protected blood vessels from damage in a mouse model of skin fibrosis, possibly by toning down GRB2.

“GRB2 appears to be a potent therapeutic target against skin fibrosis in SSc,” the researchers wrote.

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The study, “GRB2 Serves as a Viable Target Against Skin Fibrosis in Systemic Sclerosis by Regulating Endothelial Cell Apoptosis,” was published in the Journal of Dermatological Science by a team in China.

SSc, also called scleroderma, involves a buildup of fibrosis in the skin and potentially other parts of the body. It also damages the endothelial cells that line the walls of blood vessels

Most people with scleroderma develop what is known as secondary Raynaud’s phenomenon, where their fingers and toes feel numb and turn blue in response to cold temperatures. This is caused by narrowed small blood vessels, often early in disease.

How exactly this happens is unclear, but the researchers already knew that GRB2 may play a role. In earlier work, they found that the protein was toned down by salvianolic acid B, a component of the herbal medicine Danshen, and that it helped protect blood vessels from damage in models of fibrosis.

Now, the researchers analyzed samples of skin (biopsies) from 18 people with the more severe (diffuse) type of SSc and compared them with those of 15 healthy individuals. All participants were white. The levels of GRB2 messenger RNA (mRNA), the molecule that carries the instructions to make GRB2, were 1.51 times higher in SSc.

Another batch of skin biopsies from 20 Chinese people with SSc and 20 healthy individuals led to similar observations: the levels of GRB2 mRNA were increased by 1.4 times in SSc. The higher the levels of GRB2 mRNA were, the higher were those of the corresponding molecule of alpha-SMA, a marker of fibrosis.

Endothelial cells tagged, tracked

When the researchers looked at skin biopsies under a microscope, they found that GRB2 mapped mainly to endothelial cells, which had been tagged with a fluorescent red label to help distinguish them from other cell types.

To better understand the role of GRB2, the team induced skin fibrosis in mice by injecting a chemical called bleomycin under the skin in the upper back. In some of the mice, Grb2 levels were reduced (knocked down) by injecting a short string of RNA that shuts off (silences) Grb2 so that less protein is made.

Bleomycin-treated mice had thicker skin than control (healthy) mice. Their skin also was richer in collagen, a protein whose accumulation results in fibrosis. Silencing Grb2 helped prevent the skin thickening and collagen buildup caused by bleomycin.

Moreover, injection of bleomycin resulted in death (apoptosis) of endothelial cells, whereas this wasn’t observed in the bleomycin-treated mice that made less of GRB2. “These results suggest that Grb2 knockdown can inhibit endothelial cell apoptosis,” the researchers wrote.

In addition to the mouse experiments, the researchers conducted tests in the lab using endothelial cells. They exposed the cells to the chemical hydrogen peroxide to assess cell membrane permeability, a key factor in the infiltration of inflammatory cells and fibrosis.

Guarding against apoptosis

When GRB2 levels were lowered in the cells, they were protected better against hydrogen peroxide-induced increased permeability. They also were better protected against apoptosis, which was less than half as frequent as in cells with normal GRB2 levels (10.2% vs. 24.6%).

Further analysis suggested that GRB2 may act via a specific cellular pathway called focal adhesion. This involves multiple proteins that help cells adhere to and communicate with the space around them. “This pathway may play an important role in the mechanism of GRB2 in protecting endothelial cells,” the researchers wrote.

Together, these results suggest that targeting GRB2 could be a promising approach for developing treatments for SSc.