Monday , November 29 2021

LOX plays a key role in promoting skin and organ fibrosis in scleroderma


A team of researchers from the Medical University of South Carolina (MUSC) plays a major role in lysyl oxidase molecules (LOX) in scleroderma, a disorder of connective tissue that promotes skin and organ fibrosis. Researchers have shown that LOX may be useful in evaluating how an antifibrotic treatment works, suggesting that it may be potential as a biomarker of fibrosis progression or regression.

The team was led by fibrosis researcher Carol Feghali-Bostwick, Professor of SmartState and Kitty Trask Holt Scleroderma and Professor of Medicine at MUSC and a graduate of Xinh Xinh Nguyen. They report their findings in an article published online American Journal of Physiology Cellular and Molecular Physiology of the Lung.

Scleroderma is a disease of the connective tissue that causes fibrosis or thickening of organs such as the lungs, kidneys, and heart along with the skin. In fibrosis, excess connective tissue accumulates progressively around the cells of the organs, losing function and eventually failing. Historically, the only treatment offered to these patients has been lung transplantation, which is highly invasive and does not prevent fibrosis from progressing to other organs. Recently, the Food and Drug Administration approved two new drugs for pulmonary fibrosis, but their usefulness is limited in patients with scleroderma.

These medications only slow down the progression of the disease. They don’t stop. They don’t reverse. New drug targets are urgent. “

Carol Feghali-Bostwick, Ph.D., Chair of SmartState and Kitty Trask Holt Professor of Scleroderma and Professor of Medicine at MUSC.

In the study, Feghali-Bostwick and Nguyen assessed whether LOX could be a target. They were able to show that LOX plays a number of roles, known as “moonlight,” in the development and progression of fibrosis in scleroderma. The preclinical model of pulmonary fibrosis was performed using cells derived from samples from the lungs and skin tissues of patients with scleroderma and human lung and skin tissue cores. These nuclei mimic the physiological conditions of living human tissue in a real way rather than cells growing on a Petri dish.

Their findings are important because previous studies have shown that LOX exacerbates fibrosis by binding to connective tissue. The MUSC team demonstrated that LOX plays additional roles in the progression of fibrosis, stimulating the overproduction of connective tissue and increasing interleukin 6 (IL-6), an inflammatory molecule.

The research team showed that LOX expression increased 2.8-fold in the preclinical model 10 days after pulmonary fibrosis began. The research team also showed that LOX levels and activity decreased in the pulmonary fibrosis pattern, almost to baseline levels seen in the control, following the administration of an antifibrotic peptide (E4) that will soon be included in a phase 1 clinical trial. These findings suggest that measuring blood LOX activity may be a biomarker of hope for controlling the response to treatment in patients with scleroderma and other fibrotic diseases.

“LOX plays a direct role in fibrosis, and measuring circulating LOX levels is useful for monitoring the response to antifibrotic therapies,” said Nguyen, who is practicing in translational TL1 research. The training program for TL1 translational research, co-director of Feghali-Bostwick, is funded by the South Carolina Clinical & Translational Research Institute.

Feghali-Bostwick reiterated how important this fibrosis biomarker would be.

“It’s exciting to have a biomarker that goes down in LOX mice when we cause lung fibrosis and improve fibrosis,” he said. “Having a good biomarker of fibrosis would be invaluable because it would allow us to control the response to patient therapy.”

The MUSC team is researching how the E4 peptide reduces fibrosis, not only in the skin and lungs, but also in other organs. Fibrosis is the end stage of many fibroproliferative diseases that cause organ damage. There is cirrhosis, macular degeneration, and cardiovascular disease. If the E4 peptide proves to be effective in reducing fibrosis of the organs outside the lungs and skin, it could also be used as an antifibrotic therapy in these patients.

This research project was initiated by Dr. Tetsuya Nishimoto, a postdoctoral fellow at the Feghali-Bostwick Laboratory, who died unexpectedly in 2016. Thanks to Nguyen’s efforts, the Feghali-Bostwick laboratory was able to see his project to the end.


South Carolina Medical University

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