One of the hallmarks of healthy skin is its soft, smooth and pliable nature. A condition called scleroderma, or skin fibrosis, robs healthy skin of these features – making it tough, scaly and rough instead. Skin fibrosis is not just a cosmetic condition; it can sometimes be a life-threating one. Scientists have now discovered a new player involved in the development of skin fibrosis: a molecule called Fibulin-5.
The investigation reveals a hitherto unexplored mechanism involving a protein in the extracellular matrix – the substance that provides structural and biochemical support to cells in tissues. This protein, Fibulin-5, may be a key factor in promoting the stiffness and inflammation commonly seen in skin fibrosis. The team, led by Colin Jamora, from the IFOM-inSTEM Joint Research Laboratory, and bioengineering professor Shyni Varghese at the University of California, San Diego published their findings in the 15th October 2015 issue of Nature Communications.
Fibroses are disorders where stiff and fibrous connective tissues develop in organs such as the skin, lungs, heart, kidney and liver. These tissues are similar to scar tissues that grow after injuries and cause the affected areas to stiffen, swell, and eventually lose their normal function. The mechanisms underlying fibrosis development are poorly understood and the condition has no known treatment or cure.
Since about 75% of fibrotic tissue is composed of the protein collagen (~85%), most investigations on fibrosis have so far focused on studying the overproduction of this protein. However, elastin, the protein that forms elastic fibers, is also abundant in fibrotic tissue. Until now, the role of elastin in fibrosis has largely been ignored.
By focusing on elastin, the team discovered that elastic fibers contributed to fibrosis in two ways – they stiffened the tissue and promoted inflammation. Since elastin formation was known to be dependent on the molecule Fibulin-5, the researchers began to investigate the role of Fibulin-5 in skin fibrosis.
Skin levels of Fibulin-5 in mice that were genetically engineered to develop skin fibrosis were found to be much higher than in normal mice. Correspondingly, high levels of Fibulin-5 were also found in the skin tissues of human patients with skin fibrosis. This showed that the elevated levels of Fibulin-5 and the abnormally large amounts of elastin formation in fibrosis were likely to be connected.
Removing Fibulin-5 from the genetically engineered mice before they developed fibrosis put remaining doubts to rest. Fibulin-5 removal prevented all the symptoms of skin fibrosis — including skin tissue inflammation and stiffening — from occurring.
“We can now think of manipulating Fibulin-5 as a therapeutic strategy to treat skin fibrosis,” said Varghese. “With further studies, we are looking to provide hope for a disease condition that contributes to approximately 30 percent of all deaths worldwide,” adds Jamora.
As a next step, researchers are exploring methods to inhibit Fibulin-5 in fibrotic tissue to arrest the spread of the condition. Their plans also include investigations on Fibulin-5 involvement in fibrosis development in organs other than skin. One of the ultimate goals of this effort is to translate the research work on mice into life-saving therapeutic strategies to help treat fibrotic disorders.
The paper titled "The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis" and is available here: