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The Differential Effects of Two Critical Osteoclastogenesis Stimulating Factors on Bone Biomechanics Yuyu Yuan Clemson University, [email protected]

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The Differential Effects of Two Critical Osteoclastogenesis Stimulating Factors on Bone Biomechanics Yuyu Yuan Clemson University, Yyuan@Clemson.Edu Clemson University TigerPrints All Dissertations Dissertations 5-2007 The Differential Effects of Two Critical Osteoclastogenesis Stimulating Factors on Bone Biomechanics Yuyu Yuan Clemson University, [email protected] Follow this and additional works at: https://tigerprints.clemson.edu/all_dissertations Part of the Biomedical Engineering and Bioengineering Commons Recommended Citation Yuan, Yuyu, "The Differential Effects of Two Critical Osteoclastogenesis Stimulating Factors on Bone Biomechanics" (2007). All Dissertations. 416. https://tigerprints.clemson.edu/all_dissertations/416 This Dissertation is brought to you for free and open access by the Dissertations at TigerPrints. It has been accepted for inclusion in All Dissertations by an authorized administrator of TigerPrints. For more information, please contact [email protected]. THE DIFFERENTIAL EFFECTS OF TWO CRITICAL OSTEOCLASTOGENESIS STIMULATING FACTORS ON BONE BIOMECHANICS ________________________ A Dissertation Presented to the Graduate School of Clemson University ________________________ In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Bioengineering ________________________ by Yuyu Yuan May 2007 ________________________ Accepted by: Dr. Ted Bateman, Committee Chair Dr. Karen Burg Dr. Sarah Harcum Dr. Dan Simionescu Dr. Naren Vyavahare ABSTRACT Many skeletal diseases, such as osteoporosis and malignant bone metastases, are generally osteolytic and associated with increased bone resorption and decreased bone strength. Within a complex cytokine environment, the proteins RANKL and M-CSF are critical for osteoclast differentiation and activation, and thus fundamental effectors of osteolytic disorders. Previous studies showed that M-CSF stimulates the proliferation and early differentiation of osteoclast progenitors to osteoclast lineage, while RANKL targets the later stages of fusion and activation, and stimulates the formation of functional active osteoclasts. However, impacts of artificially elevated levels of these proteins on the skeleton system have not been fully characterized. In this project, we amplified the circulating levels of RANKL and M-CSF by injections or continuous administrations and examined the effects on bone volume and quality. We hypothesized that while M-CSF and RANKL can both stimulate osteoclastogenesis, the differences in activation stages targeted by these two cytokines would result in distinct responses on bone biomechanics. RANKL would directly stimulate osteoclast activity and increase bone resorption, while M-CSF would act anabolically through coupling between osteoblast development and the promoted osteoclastogenesis at the early stage, and promote bone formation indirectly. Data obtained in this project demonstrated that in vivo administration of RANKL and M-CSF induced general opposing effects on bone volume, architecture, mineralization and strength. RANKL directly stimulated bone resorption and reduceed bone biomechanical properties. The destructive skeleton induced by RANKL could serve iii as a novel animal model that exhibits a series of skeletal complications similar to those observed in osteolytic skeletal diseases, such as osteoporosis. Alternately, administrations of M-CSF markedly stimulated trabecular bone formation and had less of an influence on cortical bone. These changes demonstrated the potential of M-CSF as an anabolic agent for osteoporosis. This project has further examined the in vivo characteristics and functional effects of RANKL and M-CSF on the skeleton system. Findings in this project, such as the creation of RANKL induced bone loss model and characterization of the anabolic potential of M-CSF on the skeleton, could provide useful information and tools for further explorations on human skeletal diseases. DEDICATION This work is dedicated to my wife and my parents. I like to express my most sincere appreciations for their love and support through the course of my studies. This dissertation would not have been possible without their help and encouragement. ACKNOWLEDGMENTS First, I would like to thank my advisor Dr. Ted Bateman for his guidance, support, and encouragement throughout the course of my Ph. D study. Especially, I thank him for giving me the opportunity to conduct research in this exciting field and to collaborate with the world’s most famous biotech companies such as Amgen and Chiron, governmental agencies like National Aeronautics and Space Administration (NASA) and other national laboratories. Being a part of a new research group and starting a new research area, Dr. Bateman has provided me with crucial lessons and experience from the very beginning, which will be beneficial to me for my future careers. I would also like to thank all of my advisory committee members, Dr. Karen Burg, Dr. Sarah Harcum, Dr. Jiro Nagatomi, Dr. Dan Simionescu and Dr. Naren Vyavahare for their great support and invaluable advice in my research. I am grateful to all the current and past members of the Osteoporosis Biomechanics Laboratory for their suggestions and assistance in my research. I really enjoyed their friendship and kindness, which have been my great wealth during the period of my graduate education. I am also indebted to the faculty members, staff and fellow students in the Department of Bioengineering, for their various help during my study at Clemson University. In addition, I would also like to thank Godley Snell Research Center for their help in my animal studies. I enjoyed very much the time working with them in the animal center. vi Finally, I would like to acknowledge the funding support from National Space Biomedical Research Institute through NASA NCC 9-58, Amgen Inc., Chiron Inc., and BioServe Space Technologies (through NASA NCC8-242). TABLE OF CONTENTS Page TITLE PAGE.............................................................................................................. i ABSTRACT................................................................................................................ ii DEDICATION............................................................................................................ iv ACKNOWLEDGMENTS .......................................................................................... v TABLE OF CONTENTS............................................................................................ vii LIST OF TABLES...................................................................................................... xii LIST OF FIGURES .................................................................................................... xiii CHAPTER 1. INTRODUCTION ............................................................................................. 1 1.1 GENERAL BONE BIOLOGY............................................................................... 1 1.1.1 Component and Function....................................................................... 1 1.1.2 Bone Remodeling................................................................................... 3 1.1.2.1 Bone Resorption by Osteoclasts ................................................... 3 1.1.2.2 Bone Formation by Osteoblasts.................................................... 5 1.1.2.3 Bone Remodeling Process ............................................................ 6 1.1.3 Bone Biomechanics ............................................................................... 8 1.1.3.1 Material Properties of Bone.......................................................... 9 1.1.3.2 Structural Properties of Bone........................................................ 10 1.1.3.3 Influence of Turnover on Bone Biomechanics ............................. 11 1.2 OSTEOCLASTOGENESIS................................................................................... 13 1.2.1 Origin of Osteoclasts.............................................................................. 14 1.2.2 Regulation of Osteoclastogenesis .......................................................... 14 1.3 RANK/RANKL/OPG SYSTEM...................................................................... 19 1.3.1 Osteoprotegerin...................................................................................... 20 1.3.2 RANKL and RANK............................................................................... 22 viii Table of Contents (Continued) Page 1.3.3 RANK/RANKL/OPG System in Skeletal Diseases .............................. 24 1.4 MACROPHAGE COLONY STIMULATING FACTOR............................................. 25 1.4.1 The Central Role of M-CSF in Osteoclastogenesis ............................... 26 1.4.2 The Antiresorptive Potential.................................................................. 27 1.5 SKELETAL DISEASES ...................................................................................... 28 1.5.1 Osteoporosis........................................................................................... 29 1.5.1.1 Mechanism of Osteoporosis.......................................................... 30 1.5.1.2 Osteoporosis Therapies................................................................. 32 1.5.2 Osteolytic Bone Metastasis.................................................................... 34 1.5.2.1 Mechanisms of Osteolytic Metastases.......................................... 35 1.5.2.2 Therapeutic Approaches ............................................................... 38 1.5.3 Animal Models for Skeletal Diseases...................................................
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