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How Bone's Material Flaws Lead To Brittle Bone Disease

by Aruna on August 7, 2009 at 9:58 AM
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How Bone's Material Flaws Lead To Brittle Bone Disease

Massachusetts Institute of Technology (MIT) researchers have for the first time carried out a multi-scale analysis to shed light on how bone's material flaws lead to brittle bone disease.

The researchers say that the weak tendons and fragile bones characteristic of osteogenesis imperfecta, or brittle bone disease, stem from a genetic mutation that causes the incorrect substitution of a single amino acid in the chain of thousands of amino acids making up a collagen molecule, the basic building block of bone and tendon.

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They add that that minuscule encoding error creates a defective collagen molecule that, at the site of the amino acid substitution, repels rather than attracts the collagen molecule alongside it.

According to them, this creates a tiny rift in the tissue, which when repeated in many molecules, leads to brittle tissue, broken bones, deformity and, in the most severe form of the disease, death.
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Their analysis, published in the August 4 issue of Biophysical Journal, describes exactly how the substituted amino acid repels other amino acids rather than forming chemical bonds with them, creating a radically altered structure at the nanoscale that results in severely compromised tissue at the macroscale.

The researchers say that their approach to the study of disease, referred to as "materiomics", may prove valuable in the study of other diseases, particularly collagen- and other protein-based diseases, where a material's behaviour and breakdown play a critical role.

"The consideration of how material properties change in diseases could lead to a new paradigm in the study of genetic disorders that expands beyond the biochemical approach," said Professor Markus Buehler, of MIT's Department of Civil and Environmental Engineering.

"We wanted to see how a single-point genetic mutation in a collagen molecule could cause entire tissue to become brittle, soft and even fail. The medical community finds correlations between genetics and patients; our interest is in finding the correlation between genetics and a material's behavior," he said.

The researcher sees the application of this approach to collagen-based diseases as a starting point that could lead to a similar analysis of the mechanical properties of tissue involved in other protein-based diseases, including kidney disease Alport syndrome, Ehlers-Danlos syndrome that is characterized by overly-flexible skin and joints, and even Alzheimer's disease.

During the study, the researchers used atomistic modelling to show exactly how the substitution of eight different amino acids in place of glycine changes the electrochemical behavior of the collagen molecules, and affects the mechanical properties of the collagen tissue.

They learnt that the mutations creating the most severe form of the disease also correlate with the greatest magnitude of adverse effects in creating more pronounced rifts in the tissue, which lead to the deterioration and failure of the tissue.

"The study of how the nature of the genetic makeup influences the mechanical behavior of materials is an important frontier in bioengineering. It could potentially revolutionize the way we understand, model and treat medical disorders, and may also lead to the development of new biomaterials for applications in tissue engineering and regenerative medicine," said Sebastian Uzel, an MIT graduate student involved in the study.

Source: ANI
ARU
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