Scientists report breakthrough in bone disorder
Published: June 18, 2005
Scientists have identified the biological trigger for Van Buchem disease, a disfiguring bone condition that can cause pain, deafness and blindness.
The scientists hope their findings will eventually lead to treatments for osteoporosis and other crippling bone disorders.
“This is an extremely important project in terms of understanding the human genome, as well as health in general,” said Ivan Ovcharenko, a bioinformatics scientist at Lawrence Livermore National Laboratory who was not involved with the study.
The team included researchers from Lawrence Livermore and Lawrence Berkeley national laboratories; the Department of Energy Joint Genome Institute in Walnut Creek, Calif.; and Novartis Institutes for BioMedical Research in Switzerland.
They found that Van Buchem sufferers lack a regulatory element that directs a gene to produce a protein that controls bone formation rates.
Without this regulator, bone production goes up, thus increasing bone density.
For Van Buchem patients, this often means that bones in the skull and lower jaw thicken and enlarge, causing facial distortions and pinching nerves.
The condition can also affect collarbones, the ribs, the pelvis and other bones.
Scientists have known for several years that Van Buchem patients lack a 52,000-base-pair stretch of DNA.
DNA molecules resemble a spiral staircase, with the steps determining a person’s genetic code. Each “step” consists of pairs of molecules called bases.
The latest study takes the knowledge further by identifying within the missing stretch a 250-base-pair that functions as a light switch to activate the gene involved in bone formation rates.
“That creates a perfect target for drug therapies,” Ovcharenko said.
To investigate what causes the gene to malfunction, the scientists genetically engineered mice with and without the missing DNA segment.
They found that the bone-growth-regulating gene was dramatically less active in mice lacking the DNA segment.
The scientists then sought to identify the specific DNA sequence responsible for regulating the gene.
They first found seven DNA segments near the gene that are common in both humans and mice.
They took this approach because they assume that DNA segments “conserved” from one organism to another during evolution play an important biological role. Otherwise, they would have been discarded during the evolutionary process.
By introducing these segments into bone-forming cells and analyzing the results, the scientists were able to discover the specific segment that drives the gene activity.
Amazon discount!The findings “ultimately have the potential to identify key molecular components that can be used as new therapeutic agents to treat individuals suffering from bone loss disorders,” including osteoporosis, said Novartis team members Michaela Kneissel and Hansjoerg Keller in a statement.
Gabriela Loots of the Livermore lab’s genome biology division, who led the research team, was unavailable for comment after delivering a baby on Wednesday.
The study will be published in the July edition of Genome Research.
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