Title:
Mechanisms and Functional Implications of Aggrecan Catabolism in Cartilage and Meniscal Fibrocartilage

dc.contributor.advisor Levenston, Marc E.
dc.contributor.author Wilson, Christopher Garrison en_US
dc.contributor.committeeMember Bellamkonda, Ravi
dc.contributor.committeeMember Garcia, Anés
dc.contributor.committeeMember Sandy, John
dc.contributor.committeeMember Temenoff, Johnna
dc.contributor.department Biomedical Engineering en_US
dc.date.accessioned 2007-05-25T17:13:06Z
dc.date.available 2007-05-25T17:13:06Z
dc.date.issued 2007-04-05 en_US
dc.description.abstract Arthritis includes many conditions of the joints characterized by inflammation, pain, and loss of joint function that affect 66 million people in the U.S. alone. During arthritic degeneration, chondrocytes exhibit downregulated synthesis of extracellular matrix molecules and upregulation of proteolytic enzymes. Fibrochondrocytes, found in meniscal fibrocartilage, appear to behave in a similar way. Metalloproteinases, including matrix metalloproteinases (MMP) and a disintegrin and metollproteinase with thrombospondin motif (ADAMTS) class enzymes have demonstrated efficient, distinct aggrecan degradation in models of arthritis. ADAMTS-4 and ADAMTS-5 are thought to be primary mediators of pathologic aggrecan catabolism, while MMP-17 may be involved in ADAMTS activation. There is also growing evidence of metalloproteinase-independent mechanisms in aggrecan catabolism. The cysteine endopeptidase m-calpain has been detected in cartilage from arthritic joints, and chondrocytes can secrete this protease. The overall objective of this work was to investigate metalloproteinases and m-calpain as comediators of aggrecan turnover in articular cartilage and meniscal fibrocartilage. The central hypothesis was that metalloproteinases cooperate with m-calpain to mediate cytokine-induced aggrecan turnover and associated changes in tissue mechanics. Experiments involved using inhibitors to perturb protease systems, antibodies targeting aggrecan neoepitopes to characterize enzyme activity, and established methods of evaluating tissue compressive and shear properties. Models of degradation and de novo tissue assembly were used to investigate tissue-specific differences in aggrecan turnover. The results of this work demonstrate tissue-specific differences in the abundance and structure of aggrecan, and indicate that the mechanisms and extent of aggrecan processing in the meniscus is dependent on location within the tissue. The relationships between aggrecan structure and tissue material properties are discussed, along with implications for development, disease, and repair. en_US
dc.description.degree Ph.D. en_US
dc.identifier.uri http://hdl.handle.net/1853/14474
dc.publisher Georgia Institute of Technology en_US
dc.subject Arthritis en_US
dc.subject MMP en_US
dc.subject Aggrecanase en_US
dc.subject Material properties en_US
dc.subject Meniscus en_US
dc.subject.lcsh Articular cartilage Mechanical properties en_US
dc.subject.lcsh Arthritis en_US
dc.title Mechanisms and Functional Implications of Aggrecan Catabolism in Cartilage and Meniscal Fibrocartilage en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.corporatename Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename College of Engineering
relation.isOrgUnitOfPublication da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
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