Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils
Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular an...
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| Format: | Article |
| Language: | en_US |
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Elsevier B.V.
2015
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| Online Access: | http://hdl.handle.net/1721.1/96356 https://orcid.org/0000-0003-4540-3789 https://orcid.org/0000-0002-4173-9659 |
| _version_ | 1811074015590088704 |
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| author | Gautieri, Alfonso Vesentini, Simone Redaelli, Alberto Uzel, Sebastien Guy Marcel Buehler, Markus J |
| author2 | Massachusetts Institute of Technology. Center for Computational Engineering |
| author_facet | Massachusetts Institute of Technology. Center for Computational Engineering Gautieri, Alfonso Vesentini, Simone Redaelli, Alberto Uzel, Sebastien Guy Marcel Buehler, Markus J |
| author_sort | Gautieri, Alfonso |
| collection | MIT |
| description | Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length scales remain unknown. We show by a hierarchy of full atomistic and mesoscale simulation that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils. We find that these molecular-level changes lead to an alteration of the stress distribution in mutated collagen fibrils, causing the formation of stress concentrations that induce material failure via intermolecular slip. We believe that our findings provide insight into the microscopic mechanisms of this disease and lead to explanations of characteristic OI tissue features such as reduced mechanical strength and a lower cross-link density. Our study explains how single point mutations can control the breakdown of tissue at much larger length scales, a question of great relevance for a broad class of genetic diseases. |
| first_indexed | 2024-09-23T09:41:45Z |
| format | Article |
| id | mit-1721.1/96356 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:41:45Z |
| publishDate | 2015 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/963562022-09-26T13:09:47Z Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils Gautieri, Alfonso Vesentini, Simone Redaelli, Alberto Uzel, Sebastien Guy Marcel Buehler, Markus J Massachusetts Institute of Technology. Center for Computational Engineering Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Massachusetts Institute of Technology. Department of Mechanical Engineering Massachusetts Institute of Technology. Laboratory for Atomistic and Molecular Mechanics Gautieri, Alfonso Uzel, Sebastien GM Buehler, Markus J. Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length scales remain unknown. We show by a hierarchy of full atomistic and mesoscale simulation that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils. We find that these molecular-level changes lead to an alteration of the stress distribution in mutated collagen fibrils, causing the formation of stress concentrations that induce material failure via intermolecular slip. We believe that our findings provide insight into the microscopic mechanisms of this disease and lead to explanations of characteristic OI tissue features such as reduced mechanical strength and a lower cross-link density. Our study explains how single point mutations can control the breakdown of tissue at much larger length scales, a question of great relevance for a broad class of genetic diseases. United States. Army Research Office (grant W911NF-06-1-0291) National Science Foundation (U.S.) (CAREER Award (grant CMMI-0642545)) MIT International Science and Technology Initiatives MIT-Italy Program (Rogetto-Rocca fund) 2015-04-02T19:23:06Z 2015-04-02T19:23:06Z 2009-08 2009-02 Article http://purl.org/eprint/type/JournalArticle 00063495 http://hdl.handle.net/1721.1/96356 Gautieri, Alfonso, Sebastien Uzel, Simone Vesentini, Alberto Redaelli, and Markus J. Buehler. “Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils.” Biophysical Journal 97, no. 3 (August 2009): 857–865. https://orcid.org/0000-0003-4540-3789 https://orcid.org/0000-0002-4173-9659 en_US http://dx.doi.org/10.1016/j.bpj.2009.04.059 Biophysical Journal Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier B.V. Elsevier |
| spellingShingle | Gautieri, Alfonso Vesentini, Simone Redaelli, Alberto Uzel, Sebastien Guy Marcel Buehler, Markus J Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils |
| title | Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils |
| title_full | Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils |
| title_fullStr | Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils |
| title_full_unstemmed | Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils |
| title_short | Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils |
| title_sort | molecular and mesoscale mechanisms of osteogenesis imperfecta disease in collagen fibrils |
| url | http://hdl.handle.net/1721.1/96356 https://orcid.org/0000-0003-4540-3789 https://orcid.org/0000-0002-4173-9659 |
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