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February 05, 2004


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HARVARD GAZETTE ARCHIVES

You can't bounce back without LOX

It's what keeps you in shape

By William J. Cromie
Harvard News Office

You can't be flexible without LOX, scientists have discovered.

It's not a food or a drink, but a protein that's vital for keeping body tissues elastic - skin, lungs, large arteries, bladder, gut, and womb. The protein family is called lysyl oxidase; one of its members, LOXL1, has been found to be crucial for making elastic fibers and determining where they are located.

Li, Liu
Elastic researchers. While studying blindness, Tiansen Li (left) and Xiao Qing Liu discovered a protein that keeps skin and lungs elastic and wombs from turning inside out. (Staff photo Rose Lincoln/Harvard News Office)

Without LOXL1, the bodies of mice, and by inference humans, would suffer sagging skin, malfunctioning lungs and blood vessels, leaky bladders, and wombs that turn inside out. The protein's role was uncovered by researchers at Massachusetts Eye and Ear Infirmary, a Harvard teaching hospital in Boston. They did their experiments in mice but harbor little doubt that the results apply to humans.

"The same things may happen in humans because the genes involved are so alike," says Tiansen Li, leader of the research group and an associate professor of ophthalmology at Harvard Medical School.

Li, research fellow Xiao Qing Liu, and their colleagues were working on the causes of macular degeneration, the leading cause of age-related blindness. They focused on a layer of elastic tissue at the rear of the retina, which, when not functioning properly, can worsen the disease and lead to a loss of vision.

To find the basis of the problem, they "knocked out" various genes known to be involved in making LOX proteins. As the genes are eliminated one by one, the team checks to see what happens to the animal. Obviously, it's the kind of experiment you can't do with humans.

When they knocked out LOXL1, they saw that the animal's skin sagged and wrinkled as it would in old age. Air sacs in the lungs became enlarged as they do in humans with emphysema. The main artery (aorta) that carries blood from the heart did not expand and constrict the way it should.

All of this was expected to happen when elastic fibers in the body became weak or fail. But a bigger surprise came with the uterus. The womb is a wonderfully resilient organ. In humans, it expands to the size of a basketball to accommodate a growing fetus, then it rebounds back to the size of a pear after birth. That is, if LOXL1 works correctly. If it does not, the womb turns inside out after giving birth, a condition known as pelvic prolapse.

That's what happened to the LOXL1-less mice. "It was the most surprising part of discovering that the protein is necessary to make elastic fibers." Li says. "We had expected that collagen (which helps hold together cells and tissues) would play a major role in maintaining pelvic tissue strength."

The Massachusetts group, together with their collaborators at other research facilities in Tennessee and Texas, published their findings in the February issue of Nature Genetics.

LOXatives

Because of its critical role in supporting the body's elasticity, lack of LOXL1 may be involved in a number of diseases that plague older people: emphysema, blood vessel problems, uterine and rectal prolapses, and incontinence in elderly women. Could pinpointing the activities of a single protein led to new types of treatments for such maladies?

Li says, "that's theoretically possible if we can find a safe and effective means to deliver LOXL1, or to boost its natural production in the body. We have no plans for human trials here at Mass Eye and Ear but are willing to work with others who wish to do such experiments. In any case, it is our hope that the research results can eventually be applied to humans."

One possibility might involve a wrinkle treatment that would be less costly and last longer than Botox injections. When asked, Li noted that this thought had crossed his mind, but for now he and his colleagues plan to pursue a deeper understanding of LOXL1's potential role in age-related blindness. About 500,000 new cases of the most serious form of macular degeneration occur each year worldwide, including about 200,000 in North America.

Formation of elastic fibers in the body is a complex process. LOXL1 apparently plays a crucial role in both maintaining these fibers and in determining where they will be strung.

"Elastic fibers cannot function properly unless they cross-link and form along a scaffold," Li explains. "LOXL1 is crucial to laying new fibers onto the scaffolds. It gives spatial order to the process. Without such organization, the fibers would just clump together, something we see in older animals whose tissue have lost their resiliency."

Large blood vessels like the aorta boast elastic rings that expand and constrict their diameter. When the heart beats, squirting blood into the body's network of arteries, the aorta must expand to even out blood pressure. If not, blood pressure becomes too high, eventually damaging the arteries and the heart.

Incontinence occurs when elastic muscles surrounding the tube (urethra) that carries urine from the bladder do not open and close properly. Because of biological differences, this is a much bigger problem for elderly women than for men. It's the kind of distress for which fallout from this study might offer some relief.

"As the population of the United States ages," Li remarks, "we hope that a better understanding of LOXL1 can be a major player in the relief of many age-related diseases that have their roots in the gradual loss of elastic fibers."







Copyright 2007 by the President and Fellows of Harvard College