Bone Phenotype of Carbonic Anhydrase II Deficient and Calbindin-D28k Knockout Mice and Development of a Method to Measure In Vivo Bone Strains in Mice

Persistent Link:
http://hdl.handle.net/10150/193950
Title:
Bone Phenotype of Carbonic Anhydrase II Deficient and Calbindin-D28k Knockout Mice and Development of a Method to Measure In Vivo Bone Strains in Mice
Author:
Margolis, David Stephen
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Since the development of knockout and transgenic mouse models, mice have become the most widely used mammalian animal model to study bone. Despite the advances in knowledge of bone biology and function that have occurred from use of mouse models, many studies use primarily qualitative techniques, which may result in overlooking important subtle pathophysiologic changes. The hypothesis of this dissertation is that quantitative techniques to measure bone structure and function could identify the physiologic role of carbonic anhydrase II and calbindin-D28k in mouse bone, despite earlier qualitative studies indicating mice without these proteins have normal bone structure and function. Furthermore, a method to quantify bone function in vivo will be tested in a mouse model.Although carbonic anhydrase II deficient mice are less severely affected than patients, the mice demonstrate features of osteopetrosis including metaphyseal widening and a 50% increase in trabecular bone volume. The mice partially compensate for inhibited osteoclast function by increasing osteoclast number.Calbindin-D28k knockout mice demonstrated an increase in bone volume that results from additional bone at the endosteal surfaces. The higher bone volume results in increased stiffness and failure loads, highlighting the potential use of drugs that inhibit calbindin-D28k to treat diseases such as osteoporosis.Finally, calcium phosphate ceramic and hydroxyapatite particles used as strain gauge coatings demonstrated bone bonding to mouse femora after two months in vivo. The use of hydroxyapatite particles to coat strain gauges is the first time this method has been used with all commercially available materials, and will allow other research groups to use this technique. The major limitation to in vivo bone strain measurement in mice is the relatively large size of the sensors, which resulted in increased second moments of inertia in the implanted bones.Overall, this dissertation demonstrates that the use of quantitative techniques, including histology, histomorphometry, µCT imaging, and mechanical testing can measure subtle changes in bone properties that have been previously overlooked. Development of additional quantitative methods to study bone biomechanics in mouse models may encourage other research groups to quantify bone properties if no changes are noted using primarily qualitative methods.
Type:
text; Electronic Dissertation
Keywords:
Carbonic Anhydrase II; Calbindin-D28k; In Vivo Bone Strain Measurement
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Physiological Sciences; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Lien, Yeong-Hau H.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleBone Phenotype of Carbonic Anhydrase II Deficient and Calbindin-D28k Knockout Mice and Development of a Method to Measure In Vivo Bone Strains in Miceen_US
dc.creatorMargolis, David Stephenen_US
dc.contributor.authorMargolis, David Stephenen_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractSince the development of knockout and transgenic mouse models, mice have become the most widely used mammalian animal model to study bone. Despite the advances in knowledge of bone biology and function that have occurred from use of mouse models, many studies use primarily qualitative techniques, which may result in overlooking important subtle pathophysiologic changes. The hypothesis of this dissertation is that quantitative techniques to measure bone structure and function could identify the physiologic role of carbonic anhydrase II and calbindin-D28k in mouse bone, despite earlier qualitative studies indicating mice without these proteins have normal bone structure and function. Furthermore, a method to quantify bone function in vivo will be tested in a mouse model.Although carbonic anhydrase II deficient mice are less severely affected than patients, the mice demonstrate features of osteopetrosis including metaphyseal widening and a 50% increase in trabecular bone volume. The mice partially compensate for inhibited osteoclast function by increasing osteoclast number.Calbindin-D28k knockout mice demonstrated an increase in bone volume that results from additional bone at the endosteal surfaces. The higher bone volume results in increased stiffness and failure loads, highlighting the potential use of drugs that inhibit calbindin-D28k to treat diseases such as osteoporosis.Finally, calcium phosphate ceramic and hydroxyapatite particles used as strain gauge coatings demonstrated bone bonding to mouse femora after two months in vivo. The use of hydroxyapatite particles to coat strain gauges is the first time this method has been used with all commercially available materials, and will allow other research groups to use this technique. The major limitation to in vivo bone strain measurement in mice is the relatively large size of the sensors, which resulted in increased second moments of inertia in the implanted bones.Overall, this dissertation demonstrates that the use of quantitative techniques, including histology, histomorphometry, µCT imaging, and mechanical testing can measure subtle changes in bone properties that have been previously overlooked. Development of additional quantitative methods to study bone biomechanics in mouse models may encourage other research groups to quantify bone properties if no changes are noted using primarily qualitative methods.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCarbonic Anhydrase IIen_US
dc.subjectCalbindin-D28ken_US
dc.subjectIn Vivo Bone Strain Measurementen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairLien, Yeong-Hau H.en_US
dc.contributor.committeememberLien, Yeong-Hau H.en_US
dc.contributor.committeememberSzivek, John A.en_US
dc.contributor.committeememberRuth, John T.en_US
dc.contributor.committeememberFunk, Janet L.en_US
dc.contributor.committeememberKoshland, Gail F.en_US
dc.contributor.committeememberLai, Li-Wenen_US
dc.identifier.proquest2624en_US
dc.identifier.oclc659749612en_US
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