Don't judge this antifibrotic protein by the company it keeps

Until now, members of the IGFBP family have looked like a bad crowd. Both IGFBP-3 and IGFBP-5 are implicated in fibrosis. Fibrosis is the scarring of tissues and organs that eventually causes them to cease to function. So when IGFBP-4 instead showed antifibrotic properties, researchers at the Medical University of South Carolina (MUSC) researchers were surprised. The same family of proteins was promoting fibrosis and attempting to mount a defense against it. The results are published online ahead of print in FASEB BioAdvances.

“When you have fibrosis, there are all these proteins that promote fibrosis. But your body also makes proteins that are antifibrotic, and IGFBP-4 is one of them,” explains Carol Feghali-Bostwick, Ph.D., Kitty Trask Holt Endowed Chair for Scleroderma Research at the Medical University of South Carolina. “But ultimately you don't make enough of them. It's almost like the body is trying to heal itself. It's mounting an antifibrotic response but it's a blunted response in a lot of ways and so it never gets to where it needs to be.”

In fibrosis, cells called fibroblasts make too much collagen and other fibers, resulting in too much connective tissue. This excess connective tissue distorts the natural architecture of a tissue or organ and interferes with its function. Two of the most devastating fibrotic diseases are systemic sclerosis and idiopathic pulmonary fibrosis. Systemic sclerosis causes blood vessel damage and fibrosis in the skin, joints and internal organs and is most deadly when it affects the lungs. Idiopathic pulmonary fibrosis also results in scarring of the lung. For those with either disease whose lungs are affected, the only available treatment is transplant. But many patients cannot afford transplant or cannot find donor lungs. New therapies are much needed. So the MUSC team’s finding that IGFBP-4 is antifibrotic and could one day have potential use as a clinical agent is welcome news indeed.

Feghali-Bostwick’s team demonstrated IGFBP-4’s antifibrotic properties on the cell level, in an animal model, and in lung and skin cores.

Fibroblasts are cells that produce collagen and other fibers. Fibroblasts from lungs of patients with systemic sclerosis were compared to those from healthy controls. Levels of IGFBP-4 were markedly lower in the fibroblasts from the patients with systemic sclerosis.

Fibroblasts from systemic sclerosis patients produced less collagen after exposure to IGFBP-4. Levels of the profibrotic proteins CXCR4 and CTGF were also reduced. These studies in cells show that IGFBP-4 exerts its antifibrotic effects both directly and indirectly (via CXCR4 and CTGF).

In mice, bleomycin can be used to cause fibrosis. Bleomycin-treated mice produced less collagen and developed less lung fibrosis after receiving IGFBP-4.

Because findings in mice are not always relevant for humans, Feghali-Bostwick has developed a human organ culture model.

“It's important to understand the effects of IGFBP-4 in human tissue if you’re developing therapies,” explains Feghali-Bostwick. “Most drugs that are developed work in human cells in isolation or in mice, but they rarely work in humans when you get to the human trials. So we have this system where we take lung and skin tissues and put them in an environment that's a human-based tissue.”

Her team obtains small (3-5 mm) punches of human tissue or organ and grows them in culture into “tissue cores.” In this study, both lung and skin cores showed reduced collagen production after treatment with IGFBP-4.

Although much further work is needed before IGFBP-4 can be translated to the clinic, it does offer some advantages as a potential clinical agent. For one, its ability to counteract fibrosis on multiple fronts (directly and indirectly) could be an advantage given the large number of pathways that promote fibrosis. Second, its small size would make it less expensive to produce and less likely to cause unintended side effects.

Feghali-Bostwick will continue to study how IGFBP-4 reduces fibrosis. If she can identify which part of it is responsible for the antifibrotic effects, then only that portion of it could be administered.

“If you could just make the particular portion of the protein that is antifibrotic and not the whole protein, if you could narrow it down, it would make it less expensive to produce and less likely to have off-target effects,” explains Feghali-Bostwick.

So, it’s good news for patients with fibrotic disease that a member of the IGFBP family, which had previously been presumed to be profibrotic, is in fact antifibrotic and could one day have clinical potential. Even better news is that Feghali-Bostwick is only one of the many researchers into fibrotic disease that are making discoveries about how fibrosis works and identifying potential targets for treatment.

“What would my message be for patients with scleroderma, idiopathic pulmonary fibrosis and other types of fibrotic disease?” says Feghali-Bostwick. “I would want them to know that there are multiple potential leads like ours being developed in a lot of labs across the country and across the world. It's an exciting time because there are a lot of potential therapies being developed, and some of them are bound to work.”