Suppression of Osteoblast Activity by Disuse is Prevented by Low Magnitude Mechanical Loading through a Bone Morphogenic Protein-Dependent Mechanism A Dissertation Presented to The Academic Faculty by Mamta Jashvantlal Patel In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the School of Biomedical Engineering at the Georgia Institute of Technology and Emory University Georgia Institute of Technology April 2008 COPYRIGHT © MAMTA JASHVANTLAL PATEL 2008 Suppression of Osteoblast Activity by Disuse is Prevented by Low Magnitude Mechanical Loading through a Bone Morphogenic Protein-Dependent Mechanism Approved by: Dr. Hanjoong Jo, Chair Dr. Clint Rubin School of Biomedical Engineering School of Bioengineering School of Medicine, Division of Cardiology State University of New York at Georgia Institute of Technology Stony Brook Emory University Dr. Barbara Boyan Dr. Janet Rubin School of Biomedical Engineering School of Medicine School of Materials Science Division of Endocrinology/Metabolism Georgia Institute of Technology University of North Carolina Dr. Robert Guldberg Dr. Diana Risin School of Mechanical Engineering Space Medicine Division Georgia Institute of Technology NASA Johnson Space Center Date Approved: December 17, 2007 The important thing is not to stop questioning. Curiosity has its own reason for existing. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery every day. Never lose a holy curiosity. -Albert Einstein (1879-1955) To Ba and Dada for the heritage, Mom and Dad for the opportunities, Hemben for my childhood, Daxaben for the indomitable support, Pritty for the kindred friendship, Bhikhu for the humor, and Smita and Trisha for the future Families are like fudge...mostly sweet with a few nuts. -Author Unknown PREFACE I have been an inexorable dreamer my entire life, often aspiring for so many different ambitions that the immediate goals were frequently lost in thought. However, with every phase of my life, some things never changed. I always wanted to be just like my two older sisters, who could not be more disparate from one another. One sister wanted to be an astronaut, and thus, I, at the ripe age of seven, announced to the entire school during the morning announcements that I would one day become an astronaut. I always knew my forte embraced science and mathematics, quite contrary to the study of music, art, theatre, writing, and photography I commenced in vain. I recognized in myself a curiosity so reminiscent of scientists, and my perfectionist attitude and attention to detail often warranted teachers to suggest engineering as a profession. Thus, when sprinkled into the recipe of my life, these events led me to the Georgia Institute of Technology and Emory University in Atlanta, GA to write this dissertation in biomedical engineering. In the epigraph, I quote the great Albert Einstein’s thoughts on curiosity, a tenet that is arguably intrinsic in life. I wholly believe science requires a balance between the innate curiosity to question the reasons why certain entities exist and the acquired prudence to accept the things to which we have no answer. It is with this curiosity that science has delved into the puzzle of the human body, ascertaining the causes of pathologies that once evaded us and cultivating therapies to mitigate these medical maladies. In the spirit of Einstein’s words, I have completed my formal education by never losing my holy curiosity. From extensive “To Do” lists to three-week-in-advance experimental plans, this dissertation is brought to you after four years of diligence, vigilant thought, and an earnest aspiration to help others. Mamta Patel, Ph.D. ACKNOWLEDGEMENTS I always knew that I enjoyed science and all things scientific in school but yearned to attempt my hand at various artistic ventures, which always seemingly failed. However, in graduate school, I found a wonderful balance among my many assorted interests and even managed to find a home for creativity in science. Along the way, I met a clan of the most eclectic personalities who inspired me scientifically and dazzled me personally. To them, I owe my heartfelt thank you, for this dissertation is the product of their indomitable support, charming friendship, constant encouragement, and invasive laughter. I would like to acknowledge my advisor, Hanjoong Jo, who allowed me to work on a project related to microgravity and NASA. I am truly grateful to have been able to travel near and far to present our work at scientific sessions, which facilitated in my developing a knack for answering questions on-the-spot. My earnest admiration goes to my dissertation committee formed by Dr. Barbara Boyan and Dr. Robert Guldberg of Georgia Tech, Dr. Diana Risin of NASA, Dr. Clint Rubin of the SUNY Stony Brook, and Dr. Janet Rubin of the UNC. When we formed this committee, I was unaware that there were existing friendships among this group, making my committee meetings a joy...a sincere joy. After comments about my project had been laid on the table, the culmination of the meeting was more of a reunion of old friends. In turn, I benefited from a relaxed atmosphere of scientific discussion among mentors whose advice to me sincerely had my best interests at heart. To Dr. Boyan, thank you for taking me under your wing and leading by example in being an amazingly interesting and capturing lecturer. I am forever thankful to have had the opportunity to lecture to a room full of young undergraduates because when I first received an email saying “You make science vi fun.”, I knew teaching was in my future. To Dr. Guldberg, thank you for taking an interest in me as a person, inviting Srin and me to spend time with your beautiful (ideal) family, and for being a fantastic teacher. To Dr. Clint Rubin, your down-to-earth attitude and honest criticism have made our e-mentorship so rewarding, and to Dr. Janet Rubin, thank you for your appreciation of the details. Dr. Diana Risin, my genuine gratitude goes to you for always having my interests at the forefront of your actions. You were a wonderful mentor when I worked at NASA with the perfect balance of guidance and freedom. To the Jo lab, transitioning from the start of this uphill climb to finally reaching the summit was indeed a hike that I could not have made without the resolute support I found in your presence. You, as a whole, are an amazingly talented group of fun, intelligent, and stylish people. Waking up and coming to work for what would surely have been a dreadful balance between classes and research ended up being one of my favorite things to do because of your shining personalities. Of course, all sorts of mad love and thank yous go to Tress, Ames, and Rando for being three of the coolest people I have ever met! Tress, I can still remember meeting you at recruiting weekend and thinking you were such a sweet person. It was a most pleasant surprise to find that you had joined the same lab as I, and it was instantly apparent that we would share this frustrating, undulating, and exhilarating journey with persistent support and unwavering friendship. During these past four and a half years, we have laughed, shared, shopped, failed, succeeded, and persevered together. I am truly most fortunate to have had you along the way. Your sense of humor, innate quality for baking desserts, and enviable “nice” attribute make you a marvelous friend. We have often remarked that you and Pritty are identical, and as such, I often feel like you are my own sister. vii Ames, my wonderful, beautiful, words-do-not-do-justice-to-you Ames. It often feels like speaking to you is like looking in a mirror. You read my mind with uncanny accuracy, and together we have celebrated our ups and commiserated our downs. I secretly hoped you would join our lab when you rotated that summer, but I never imagined we would form a friendship that is without a doubt centered about a sincere appreciation for each other. I have lived and learned vicariously through your beautiful marriage, and I am eternally thankful to have had a friend who just “got it”. Thank you for the laughter, the tears, the successes, and the lessons. You truly are a remarkable person. I actually cannot wait to share our future with each other. Rando, you quickly became one of my favorite friends for your ability to listen and sincere love of music. Thank you for keeping me hip enough to listen to music outside of my country-filled iTunes. My many thanks go to you for sharing in my joy of college football, and Thanksgiving day games with you were one of the highlights of my years here in ATL (sorry I missed this year). I do not know if I will ever hear the words South Dakota without thinking of my farm friend Randy! For you, I would actually go to Yankton. Maria, thank you for your no-holds-barred attitude and for being an awesome lab manager! Michelle, thank you for always being an open ear for my venting, sharing your drama-filled personal life with me ☺, for changing my media from those annoying Opticells, for not making me feel bad when I asked you to change my media, and for taking the time to listen to me no matter how busy you were. Dr. Hannah Song, thank you for always bringing a smile to work and being a wealth of information on those darn BMPs.