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Científicos de Stanford / Packard aceleran el sanado de hueso dañado

Stanford/Packard scientists speed healing of bone damage

By Krista Conger

STANFORD, Calif. — Blocking a naturally occurring inhibitor of bone formation accelerates healing of skull defects in mice, say researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital. The finding advances the understanding of how the skeleton develops and opens new therapeutic avenues for many of the disorders that are expected to afflict aging baby boomers.

“This could potentially lead to much more effective therapies for how we replace bone or promote bone healing,” said Michael Longaker, MD, professor of plastic and reconstructive surgery. “Let’s say I’m an 80-year-old with a fractured hip. It would be invaluable to be able to heal more quickly and regain mobility and strength.”
The study will be published in the Sept. 7 issue of the Journal of Biological Chemistry. Scientists have known for some time about a class of proteins called bone morphogenetic proteins, or BMPs, which stimulate bone formation. In fact, some current therapies for stimulating bone formation, such as spinal fusions, use recombinant BMPs to help healing. But Longaker’s new study of a protein called Noggin, which blocks bone growth, suggests there might be another, more efficient approach.

Noggin was first identified in 1992 by one of Longaker’s collaborators, Richard Harland, PhD, now a faculty member at the University of California-Berkeley, as a protein that guides tissue fate in developing frog embryos. In 2003, the researchers found that Noggin prevents the premature fusion of bones in the skull during infancy by blocking the actions of BMPs.

Longaker and the first author of the new study, Derrick Wan, MD, a postdoctoral scholar at Stanford, wondered whether interfering with Noggin expression could speed bone growth. In the new study, they initially found through work with tissue cultures that using small pieces of RNA to block Noggin expression in bone-forming cells increased the activity of the cells’ BMPs and nudged them further down the bone-producing path. Furthermore, bone-forming cells in which Noggin expression was suppressed were able to heal large skull defects in mice significantly more quickly than Noggin-expressing cells.

“Basically we just took away the natural brake and let the accelerator go to town,” said Longaker, who is also a pediatric craniofacial surgeon at Packard Children’s Hospital. Despite the accelerated rate of healing seen in the mice treated with the Noggin-challenged cells, bone formation didn’t run rampant in these animals. After eight weeks, the healed skulls of the two groups of mice looked similar. This is important because over-enthusiastic bone formation could exacerbate rather than solve musculo-skeletal problems.

“The bone that was formed looked very normal,” said Longaker. “It’s not as if these mice grew horns or anything.”

In addition to the obvious therapeutic implications, the discovery of the interplay between Noggin and BMPs also sheds light on a perplexing developmental mystery: What guides skeletal formation during embryogenesis, when BMPs are expressed in many cells not destined to become bone? Now it appears that Noggin, along with other potent BMP inhibitors, keeps the BMPs in check throughout most of the body. This type of yin-yang relationship keeps the body primed to respond quickly to damage like fractures.

Although the concept needs to be tested in humans, the researchers envision a day when many disorders could benefit by tweaking Noggin levels up or down.

“Think of the way we treat arthritis,” said Longaker. “Right now, we cut off the diseased part of the joint and glue in a metal implant. Imagine if we could instead use a biodegradable replacement seeded with a compound that could knock down Noggin expression in the area and slowly secrete BMPs. Over two or three years, the implant would dissolve, to be replaced by the individual’s own healthy bone. This is a first step toward the concept of personalized bone tissue engineering.”

In addition to Wan, Longaker’s Stanford collaborators include Jason Pomerantz, MD, postdoctoral scholar; Jae-Beom Kim, PhD, research associate; and Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor of Pharmacology. Longaker also collaborated with researchers at UCLA.

The research was funded by the National Institutes of Health , the Oak Foundation, a Ruth L. Kirschstein National Research Service Award, and an Ethicon-Society of University Surgeons Research Fellowship.

Courtesy of Stanford School of Medicine

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