Tumor suppressor may attenuate fibrotic disease

Feb 17, 2009

New research reveals a critical cellular signaling pathway that is responsible for generating excess connective tissue in multiple organs, similar to what is seen in human patients with scleroderma. The study, published by Cell Press in the February issue of the journal Developmental Cell, also reveals an intriguing but unexpected regulatory role for a tumor suppressor gene in fibrotic disease.

Platelet derived growth factors (PDGF) regulate the proliferation, survival, migration and differentiation of cells and play a critical role during embryonic development. However, the consequences of excess PDGF signaling are not very well understood.

"Aberrant PDGF signaling has been implicated in diverse fibrotic conditions where connective tissue cells called fibroblasts proliferate and deposit excessive connective tissue, leading to progressive scarring and organ dysfunction," says senior study author, Dr. Philippe Soriano from the Mount Sinai School of Medicine in New York."For example, human scleroderma patients, who characteristically exhibit widespread fibrosis, possess antibodies that activate PDGF receptors."

Dr. Soriano and Dr. Lorin E. Olson, who conducted this work initially at the Fred Hutchinson Cancer Research Center in Seattle and then pursued it at Mount Sinai, developed a mouse model in which they could selectively activate the PDGF receptor alpha (PDGFR?) during embryonic development and in adult animals.

The researchers found that elevated PDGFR? signaling led to aberrant overgrowth of connective tissue. In adults, this led to a progressive fibrosis in multiple organs. Interestingly, loss of the tumor suppressor Ink4a/Arf dramatically accelerated the development of fibrotic lesions. This finding suggests that cells may attenuate the effects of PDGFR? signaling through an Ink4a/Arf-dependent mechanism.

The study provides insight into the signaling pathways involved in connective tissue disease and highlights a new role for tumor-suppressors in the regulation of fibrotic conditions. "Our findings provide direct evidence that increased PDGFR? signaling can be sufficient to drive systemic connective tissue disease in organ systems that are relevant to human scleroderma," concludes Dr. Soriano. "The work also establishes an excellent animal model for testing novel therapeutic approaches for blocking aberrant PDGFR? signaling in human disease."

Source: Cell Press

Explore further: Scientists show that evolution of complex bioluminescent traits may be predictable

add to favorites email to friend print save as pdf

Related Stories

Amphibians being wiped out by emerging viruses

42 minutes ago

Scientists tracing the real-time impact of viruses in the wild have found that entire amphibian communities are being killed off by closely related viruses introduced to mountainous areas of northern Spain.

Dispelling a misconception about Mg-ion batteries

1 hour ago

Lithium (Li)-ion batteries serve us well, powering our laptops, tablets, cell phones and a host of other gadgets and devices. However, for future automotive applications, we will need rechargeable batteries ...

Are male brains wired to ignore food for sex?

1 hour ago

Choosing between two good things can be tough. When animals must decide between feeding and mating, it can get even trickier. In a discovery that might ring true even for some humans, researchers have shown that male brains ...

That pregnant feeling makes a fly start nesting

1 hour ago

Across the animal kingdom, it's not uncommon for pregnancy to change an expectant mom's behavior. Even female flies have their own rudimentary way of "nesting," which appears to be brought on by the stretch ...

Recommended for you

Secret wing colours attract female fruit flies

2 hours ago

Bright colours appear on a fruit fly's transparent wings against a dark background as a result of light refraction. Researchers from Lund University in Sweden have now demonstrated that females choose a mate ...

Crowdsourced power to solve microbe mysteries

4 hours ago

University of New South Wales scientists hope to unlock the secrets of millions of marine microbes from waters as far apart as Sydney's Botany Bay and the Amazon River in Brazil, with the help of an international ...

Pigeons and people play the odds when rewards are higher

5 hours ago

(Phys.org) —If you were weighing the risks, would you choose to receive a guaranteed $100, or take a 50/50 chance of winning either $200 or nothing? Researchers at the University of Alberta have shown that ...

User comments : 0