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Cartilage mechanobiology : the effects of loading on the fine structure and function of chondroitin sulfate glycosaminoglycans

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dc.contributor.advisor Alan J. Grodzinsky. en_US Szafranski, Jon D. (Jon David) en_US
dc.contributor.other Massachusetts Institute of Technology. Biological Engineering Division. en_US 2006-08-25T18:52:46Z 2006-08-25T18:52:46Z 2005 en_US 2005 en_US
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005. en_US
dc.description Includes bibliographical references. en_US
dc.description.abstract Chondroitin sulfate is a critical component of articular cartilage due to its contribution to the tissue's resistance to compressive deformation. Alterations in the biosynthesis of this molecule over time could impact the ability of the tissue to perform its necessary functions. Several factors have been shown to alter the biosynthesis of chondroitin sulfate in cartilage; among them are age, disease, depth of tissue, and mechanical compression. Specifically, mechanical compression has been shown to have a significant effect on the sulfation pattern and chain length and number in cartilage explant studies. The mechanisms that govern these alterations, however, have not been determined. The purpose of this study is to examine the effects of mechanical compression on chondroitin sulfate biosynthesis and analyze the roles of two possible mechanisms; enzyme transcription and organelle deformation. The effects of mechanical compression on the transcription rates of enzymes associated with the biosynthesis of chondroitin sulfate have not been previously studied. To perform this study in a bovine model, portions of the bovine genome had to be sequenced, PCR primers designed, and bulk expression levels determined. Static compression resulted in the significant up-regulation of two genes of interest: chondroitin sulfate and GalNAc 4S,6-sulfotransferase. en_US
dc.description.abstract (cont.) Dynamic compression resulted in the significant up-regulation of the three sulfotransferases responsible for the bulk of sulfation in cartilage tissue. These results indicate a transient mechanotransduction reaction that differs based on the load regime. The effect of mechanical loading on the biosynthesis of chondroitin sulfate has been studied previously, however, this study seeks to examine more comprehensive loading regimes. Static compression and release resulted in an increase in 6-sulfation and a decrease in 4-sulfation that lasted to 48 hours after release of compression. Dynamic compression and release had the opposite effect on sulfation ratio, with an increase in 4-sulfation compared to 6-sulfation. The transcription changes seen in this study do not indicate the changes that occur in the end products of synthesis. Other factors may play a larger role, such as precursor availability or transport through the Golgi apparatus. Intracellular organelles react to static compression of the surrounding tissue in one of two manners. The majority of organelles deform much as the nucleus, proportionally in volume and shape to the cell. The Golgi apparatus appears to retain a significant portion of its volume relative to the cell and other organelles. In addition, it reforms structurally into a highly ordered stacked appearance. en_US
dc.description.abstract (cont.) Osmotic forces within the Golgi may allow it to balance the osmotic load in the cytoplasm and resist compression and altered trafficking of the Golgi may in turn produce the altered appearance. Recent microscopy experiments on the Golgi apparatus utilizing two-photon microscopy have allowed us to examine the reaction of live tissue to static compression. These results illustrate the significant, but differing, effects of static and dynamic compression on the biosynthesis of chondroitin sulfate. The effects of these compression types on the transcription of enzymes responsible for this biosynthesis cannot fully explain the changes seen in newly synthesized chondroitin sulfate. Organelle reorganization has been shown to occur in response to static load and it is possible that altered organelle trafficking plays a role in this altered biosynthesis. Further studies are necessary to determine the final effect of the altered transcription and organelle structure on the manufacture of this important cartilage molecule. en_US
dc.description.statementofresponsibility by Jon D. Szafranski. en_US
dc.format.extent 128 leaves en_US
dc.format.extent 6524773 bytes
dc.format.extent 6530410 bytes
dc.format.mimetype application/pdf
dc.format.mimetype application/pdf
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.subject Biological Engineering Division. en_US
dc.title Cartilage mechanobiology : the effects of loading on the fine structure and function of chondroitin sulfate glycosaminoglycans en_US
dc.title.alternative Effects of loading on the fine structure and function of chondroitin sulfate glycosaminoglycans en_US
dc.type Thesis en_US Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.identifier.oclc 66464336 en_US

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