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Relationships Between Decorin and Biglycan, Structure and Tendon Mechanics Using Mutant Mouse Models

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Relationships Between Decorin and Biglycan, Structure and Tendon Mechanics Using Mutant Mouse Models University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2011 Relationships Between Decorin and Biglycan, Structure and Tendon Mechanics Using Mutant Mouse Models LeAnn Dourte University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biomechanics Commons Recommended Citation Dourte, LeAnn, "Relationships Between Decorin and Biglycan, Structure and Tendon Mechanics Using Mutant Mouse Models" (2011). Publicly Accessible Penn Dissertations. 503. https://repository.upenn.edu/edissertations/503 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/503 For more information, please contact [email protected]. Relationships Between Decorin and Biglycan, Structure and Tendon Mechanics Using Mutant Mouse Models Abstract Tendons have a complex mechanical behavior that depends on their composition and structure. Understanding structure-function relationships may elucidate important differences in the functional behaviors of specific tendons and guide targeted treatment modalities and tissue engineered constructs. Specifically, the interactions of small leucine-rich proteoglycans (SLRPs) with collagen fibrils, association with water and role in fibrillogenesis suggest that SLRPs may play an important role in tendon mechanics. Some studies have assessed the role of SLRPs in the mechanical response of tendon, but the relationships between sophisticated mechanics, assembly of collagen and SLRPs have not been well characterized. Therefore, the aim of this study was to evaluate the structure-function relationships between complex tendon mechanics, structure and composition with a focus on decorin and biglycan, two Class I SLRPs. Utilizing homozygous null and heterozygous mutant genotype mouse models, the amount of SLRPs were varied to allow for the study of the "dose" response on tendon mechanics. A statistical model was used to explore the coordinated roles of the measured matrix molecules to better understand the structure-function relationships in tendon and account for compensation often seen in mutant models. In the decorin and biglycan mutant genotype mice, no changes were seen in any elastic tensile or compressive properties compared to wild type. However, viscoelastic mechanical properties were altered in decorin heterozygotes and biglycan nulls and heterozygotes. Compensatory increases in the expression of other SLRPs were noted in the biglycan mutant genotypes. Changes were also found in total collagen content and collagen structure, although collagen characteristics could not completely explain the viscoelastic changes measured. These results suggest that decorin and biglycan play a role in tendon viscoelasticity. Finally, a multiple regression statistical model was used to determine the compositional and structural components that predict mechanical properties. Challenges with this type of model with small tissue size were discussed. Complex interactions between SLRPs and collagen were present in all models and demonstrate the importance of considering the amounts of other components in the tissue when examining structure-function relationships. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Bioengineering First Advisor Louis J. Soslowsky Keywords biglycan, decorin, proteoglycans, SLRP, structure-function, tendon Subject Categories Biomechanics This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/503 RELATIONSHIPS BETWEEN DECORIN AND BIGLYCAN, STRUCTURE AND TENDON MECHANICS USING MUTANT MOUSE MODELS LeAnn M. Dourte A DISSERTATION In Bioengineering Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2011 Supervisor of Dissertation __________________________ Louis J. Soslowsky, PhD, Fairhill Professor, Orthopaedic Surgery Graduate Group Chairperson __________________________ Beth A. Winkelstein, PhD, Professor, Bioengineering Dissertation Committee Susan S. Margulies, PhD (Committee Chair) Professor, Bioengineering, University of Pennsylvania David E. Birk, PhD Professor, Pathology & Cell Biology, University of South Florida Dawn M. Elliott, PhD, Professor, Biomedical Engineering, University of Delaware G. Russell Huffman, MD, MPH Assistant Professor, Orthopaedic Surgery, University of Pennsylvania Acknowledgements I would first like to thank the members of my committee for guiding me through the graduate experience. I would especially like to thank Dr. Louis Soslowsky, my advisor, for his commitment to teaching and mentoring and providing support, knowledge, and insight throughout my time here. I thank Dr. David Birk for his insight and help in the planning, execution and analysis of this work. I also thank Dr. Dawn Elliott, Dr. Susan Marguiles and Dr. Russell Huffman for their valuable comments and suggestions throughout my studies. I’d also like to thank the members of the McKay Orthopaedic Research Laboratory, past and present, who have been fantastic friends, colleagues and mentors. In particular, I thank Dr. J Sarver for providing guidance and support on technical and non- technical topics alike. I thank David Beason for his help in solving computer, equipment and pretty-much-anything-else problems. I am grateful to Dr. Cathryn Peltz for her mentorship and continued support. I also thank Lydia Pathmanathan for her help and persistence and who is responsible for much of this work. I would also like to acknowledge the members of the Birk lab for their enormous help in collecting and analyzing the data in this thesis. Finally, none of this would have been possible without the love and support of my family. I thank my parents, Dale and Joyce, who have always believed in me. I thank my sister, Emily, who is always ready to make me laugh if needed. And finally, I thank Andrew, for his endless hours of support and patience. ii ABSTRACT RELATIONSHIPS BETWEEN DECORIN AND BIGLYCAN, STRUCTURE AND TENDON MECHANICS USING MUTANT MOUSE MODELS LeAnn M. Dourte Louis J. Soslowsky Tendons have a complex mechanical behavior that depends on their composition and structure. Understanding structure-function relationships may elucidate important differences in the functional behaviors of specific tendons and guide targeted treatment modalities and tissue engineered constructs. Specifically, the interactions of small leucine-rich proteoglycans (SLRPs) with collagen fibrils, association with water and role in fibrillogenesis suggest that SLRPs may play an important role in tendon mechanics. Some studies have assessed the role of SLRPs in the mechanical response of tendon, but the relationships between sophisticated mechanics, assembly of collagen and SLRPs have not been well characterized. Therefore, the aim of this study was to evaluate the structure-function relationships between complex tendon mechanics, structure and composition with a focus on decorin and biglycan, two Class I SLRPs. Utilizing homozygous null and heterozygous mutant genotype mouse models, the amount of SLRPs were varied to allow for the study of the “dose” response on tendon mechanics. A statistical model was used to explore the coordinated roles of the measured matrix molecules to better understand the structure-function relationships in tendon and account for compensation often seen in mutant models. In the decorin and biglycan mutant genotype mice, no changes were seen in any elastic tensile or compressive properties iii compared to wild type. However, viscoelastic mechanical properties were altered in decorin heterozygotes and biglycan nulls and heterozygotes. Compensatory increases in the expression of other SLRPs were noted in the biglycan mutant genotypes. Changes were also found in total collagen content and collagen structure, although collagen characteristics could not completely explain the viscoelastic changes measured. These results suggest that decorin and biglycan play a role in tendon viscoelasticity. Finally, a multiple regression statistical model was used to determine the compositional and structural components that predict mechanical properties. Challenges with this type of model with small tissue size were discussed. Complex interactions between SLRPs and collagen were present in all models and demonstrate the importance of considering the amounts of other components in the tissue when examining structure-function relationships. iv Table of Contents Acknowledgements ............................................................................................................. ii ABSTRACT ....................................................................................................................... iii Table of Contents ................................................................................................................ v List of Figures .................................................................................................................... xi Chapter 1. Introduction ....................................................................................................... 1 A. Introduction ............................................................................................................... 1 B. Background ............................................................................................................... 3 B1. Tendon Structure and Composition ...................................................................
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