Wound Healing Enzyme Implicated in Mystery Fibrosis

WINSTON-SALEM, N.C., Sept. 25 -- Activation of transglutaminase-2 (TG2) may trigger the mysterious and debilitating fibrosis that affects some end-stage renal patients, researchers here believe.

In a pilot study using stored tissue, an enzyme involved in wound healing was markedly increased in the skin of patients who suffered nephrogenic systemic fibrosis (NSF), according to David Sane, M.D., of Wake Forest University Baptist Medical Center and colleagues.

The rare condition occurs in some end-stage renal patients after they undergo magnetic resonance imaging using a gadolinium-based contrast agent, Dr. Sane and colleagues noted in the October issue of the American Journal of Dermatopathology.

"The cause of this syndrome has been unclear," Dr. Sane said in a statement. "Our research suggests both a potential cause and the possibility of preventing or treating NSF."

The condition is characterized by dermal fibrosis, increased immature dermal collagen, mucin, and spindle cells within the dermis and subcutaneous septa, the researchers said.

Patients experience contractures of the joints, pain, and itching, although the condition can also lead to fibrosis of internal organs such as the heart and lung.

While the cause of nephrogenic systemic fibrosis is unknown, research has shown that gadolinium accumulates in the tissues of people with the condition, he said.

It's also known that gadolinium activates a class of enzymes known as tissue transglutaminases - including transglutaminase-2 (TG2) and factor XIIIa (FXIIIa) -- which cross-link glutamine and lysine residues of proteins, forming isopeptide bonds.

Dr. Sane and colleagues hypothesized that the transglutaminases would be highly expressed in tissue from people with NSF and not in normal tissue.

To test the idea, they use immunohistochemical techniques to compare tissue samples from five patients with the fibrosis to samples from three healthy controls.

In a blinded fashion, three pathologists rated levels of TG2, factor XIIIa, transglutaminase isopeptide, and the histiocyte marker CD68 as strong, moderate, or weak.

The spindle cells and histiocytes in all patients with nephrogenic systemic fibrosis were positive for TG2 and FXIIIa, while the rare spindle cells of normal skin were negative for TG2 and only weakly positive for FXIIIa, the researchers found.

"Compared with the healthy subjects, there was a marked increase in TG2 in the [patients] with NSF," Dr. Sane said. "This suggests that activation of TG2 can produce the syndrome. "

Also, he added, TG2 is expressed in virtually all tissues, which "may explain why the fibrosis can occur in the heart and lungs, as well as the skin."

The researchers noted that the study is limited by its small size and suggested that further research is needed to pin down the role of the transglutaminases in NSF.

Earlier this year, the FDA asked makers of contrast agents to include a warning on gadolinium-based agents, alerting health-care professionals to the risk of nephrogenic systemic fibrosis. (See: FDA Orders Black Box Warning for Gadolinium-Based Contrast Agents)

"Solving this puzzle might allow dialysis patients to take full advantage of the diagnostic capabilities of MRI," said co-author Gil Yosipovitch, M.D., a dermatologist at Wake Forest.

Dr. Sane added that the link between gadolinium and the transglutaminases "could be a general mechanism for a broad range of disorders that involve fibrosis."