There’s a lot of give, stretch and elasticity to large blood vessels, tendons, ligaments and heart muscle. That compliant behavior is the work of a yellowish mucoprotein called elastin, the main connective-tissue protein of such stretchable structures. Elastin’s main enemy in the body is pulmonary emphysema, which leaves its victims wheezing and gasping not just for breath but for therapeutic snortfuls of pure inhaled oxygen.

“Elastin,” observed molecular biologist Eric Olson, at the University of Texas Southwest Medical Center in Dallas, “is a secreted protein that organizes long polymers, to which cells attach themselves. It provides structure and elasticity to tissues. Tropoelastin,” he added, “is the actual monomeric form of elastin that is polymerized to form the pulmonary elastin polymers. There are other protein components to elastin, some of which have been identified, some of which have not.”

Olson is senior author of a paper in the current issue of Nature, dated Jan. 10, 2002. It bears the title: “Fibulin-5 is an elastin-binding protein essential for elastic fiber development in vivo.”

Back to back in the same issue of Nature is a companion article titled: “Fibulin-5/DANCE is essential for elastogenesis in vivo.” Its senior author is cardiologist Kenneth Chien, director of molecular medicine at the University of California at San Diego. That paper’s first author is Tomoyuki Nakamura, a UCSD project scientist. (The acronym “DANCE” stands for “Developing Arteries and Neural Crest Epidermal growth factor-like.”)

“The major finding of our paper,” Olson told BioWorld Today, “is that we discovered a novel and unanticipated function of the fibulin-5 protein. We found that it is required for elasticity of tissues and organs skin, vascular system, lungs. It was an unanticipated discovery that the protein functions as an elastin receptor, which binds and organizes elastin and couples it to cells.”

Fibulin-5, a secreted protein of 448 amino acids with a relative molecular mass of 66,000, is strongly expressed by developing arteries. Elastin is the stretchable molecule that gives lungs and bronchial tubes the flexibility they need for breathing.

Scoping Emphysema’s Molecular Mechanism

“An enormous amount of research has been done on elastin biochemistry over many years,” Olson continued, “but the precise mechanism that organizes elastin and links it to cells has been elusive. So this Nature paper provides a mechanistic explanation for how elastin is linked to cells. It also sheds potential light on mechanisms for loss of elasticity of skin, as well as a potential molecular basis for emphysema.

“We discovered fibulin-5 several years ago in a complementary DNA subtraction screen,” Olson went on. “We were looking for novel proteins that were highly expressed in vascular smooth muscle cells. When we discovered it, we were extremely interested in its expression pattern, which marked skin, vasculature and the valves of the heart. But we did not know what the function of fibulin-5 was,” Olson recounted, “so for that reason we generated knockout mice lacking the fibulin-5 gene. These KO animals developed extremely loose skin and sagging jowls, senescent appearance and excess folds of abdominal skin. And those abnormalities became more pronounced with age.

“When we did detailed postmortem anatomical studies on the mice,” Olson continued, “we found that by approximately 50 days of age, homozygous KO mice that is, lacking fibulin-5 had severe pulmonary and vascular abnormalities. Their lungs were expanded with emphysema, and contained dilated alveoli. Their aortas were tortuous and elongated. While these aortic and pulmonary anomalies were apparent at postnatal day one in every fibulin-5-minus mouse, heterozygous mice, lacking only one allele, were normal and healthy.

“Fibulin-5’s gene, although we’ve studied it in the mouse,” Olson pointed out, “is highly conserved in the human genome. So it’s probably playing the same elasticity role in the human condition. Whether this gene is involved in the normal processes of aging wrinkling and sagging of skin, the cutis laxa syndrome in humans and changes in the lungs and vascular systems, is an extremely interesting issue that we plan to pursue.

“It’s also of interest,” Olson added, “to consider what the function of this protein might be in processes of wound healing or in abnormalities of the vascular system, which require elasticity of the cells and tissues for wound repair. So we can now use this KO mouse as a model system to investigate those lesions.”

How About A Gene Therapy Face-Lift?

Olson made another observation: “One can also think about possible gene therapy approaches. One might wish to introduce fibulin-5 genes into the area of a wound and ask whether it could enhance tissue repair.” He suggested, “We may try that in our mice doing a biological face-lift.”

As for the apparently virtually identical companion Nature paper by the San Diego scientists, Olson commented: “The phenotypes are identical but the papers are complementary. The reason is that in our paper we showed that fibulin-5 binds directly to elastin through a calcium-dependent mechanism. In Chien’s paper, he showed that fibulin-5 binds directly to the surfaces of cells. So if you put conclusions of the two papers together it leads to a more integrated view of fibulin-5’s function. That protein is a linker, a receptor for elastin, which links elastin to the surface of cells. So when you get rid of this protein in KO mice, their cells could no longer respond to elastin, and they no longer have elasticity.”

Nakamura, the UCSD paper’s first author, made the point, “The elastic fiber system is essential in the structure and function of various types of organs that require elasticity. Currently, it is not known,” he noted, “how elastic fibers develop; thus, there is no way to develop elastic fiber, which tends to degrade in aging and in some diseases.”

Besides similar aortic and lung hallmarks in fibulin-5 KO mice, the UCSD team reported “ruptured air sacs and bubble-like spaces throughout the emphysematous lungs, similar to human emphysema where elastic fibers are degraded.” In some of the mice they noted pelvic hernias and enlarged gallbladders and spleens.

“We believe that defects in the fibulin-5/DANCE pathway could play an important role in emphysema,” observed the paper’s senior author, Chien. “The next step,” he concluded, “will require the precise identification of the fibulin-5/DANCE receptor.”