Mechanism Underlying Fibrosis in RDEB Could Be New Therapeutic Target

In the absence of collagen 7, the protein missing in recessive dystrophic epidermolysis bullosa (RDEB) patients, the protein thrombospondin-1 (TSP1) plays a key role in the development of fibrosis, or scarred tissue.

This newly discovered mechanism suggests TSP1 as a potential therapeutic target for RDEB patients.

The study, “Thrombospondin-1 is a major activator of TGF-beta signaling in recessive dystrophic epidermolysis bullosa fibroblasts,” was published in the Journal of Investigative Dermatology.

Epidermolysis bullosa (EB), also known as butterfly syndrome, comprises several genetic skin disorders that alter the way skin develops, leading to blistering. The types of EB are determined by the layer of the skin where blisters form.

Dystrophic epidermolysis bullosa (DEB) is caused by a lack of collagen 7, a protein necessary for wound healing and adhesion of the skin under the basement membrane.

This condition is characterized by fibrosis — scarring of the connective tissue — when the blisters heal. This causes extensive scarring of the skin that results in the fusion of fingers and toes.

The more severe form of the disease appears when a person inherits two mutated copies of the gene holding the instructions to produce collagen 7, called recessive DEB (RDEB).

Different mechanisms can lead to fibrosis; one of them depends on the activation of a protein called transforming growth factor-beta (TGF-beta) by another protein called thrombospondin-1 (TSP1).

Skin cells of people with RDEB have more of these proteins than healthy individuals. However, the exact mechanisms leading to fibrosis were not well-understood.

Now, researchers have unraveled the mechanism by studying the association between these molecules in cells extracted from RDEB patients.

They found that in healthy individuals, collagen 7 sequesters TSP1, which prevents TSP1 from activating TGF-beta, thus decreasing fibrosis. However, because collagen 7 is reduced or lacking in RDEB, TSP1 is continually activating TGF-beta and causing fibrosis.

“Our data points to that being the major driver of fibrosis in these patients,” Andrew South, PhD, senior author of the study, said in a press release.

“We identify TSP1 as a mediator of fibrosis in RDEB that can potentially be pharmacologically targeted to reduce TGFβ signaling in patients,” the study concluded. “While this approach will not replace [collagen] C7 in RDEB patients, it has the potential to ameliorate significant complications in this severe condition.”

The researchers found a molecule that prevents TSP1 from activating TGFβ in a tissue model that simulated skin affected by RDEB. They are also evaluating some 1,500 approved substances to see whether one of them can block the interaction of TSP1 and TGF-beta.

“Now that we know one of the major activators of fibrosis is TSP1, we’re looking to see whether it’s possible to repurpose any of those drugs to treat fibrosis in butterfly syndrome patients,” South said.