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Osteoclast Ontogeny-Experimental Studies in Two Osteopetrotic Mutations in the Rat: a Dissertation

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Osteoclast Ontogeny-Experimental Studies in Two Osteopetrotic Mutations in the Rat: a Dissertation University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 1994-04-01 Osteoclast Ontogeny-Experimental Studies in Two Osteopetrotic Mutations in the Rat: A Dissertation Matthew Joseph Cielinski University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Animal Experimentation and Research Commons, Digestive System Commons, Genetic Phenomena Commons, Musculoskeletal Diseases Commons, and the Stomatognathic System Commons Repository Citation Cielinski MJ. (1994). Osteoclast Ontogeny-Experimental Studies in Two Osteopetrotic Mutations in the Rat: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/0yw8-qj34. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/141 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. OSTEOCLAST ONTOGENY-EXPERIMENTAL STUDIES IN TWO OSTEOPETROTIC MUTATIONS IN THE RAT A Dissertation Presented Matthew Joseph Cielinski Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of: DOTOR OF PHILOSHY IN MEDICAL SCIENES April 1994 Cell Biology This dissertation is dedicated to my wife, Jil. You have shared my dreams, your love and friendship have made them possible. (9 1994 MATTHEW J. CIEUNSKI AL RIGHTS RESERVED iv OSTEOCLAST ONTOGENY-EXPERIMENTAL STUDIES IN TWO OSTEOPETROTIC MUTATIONS IN THE RAT A Dissertation Presented By Matthew Joseph Cielinski Approved as to style and content by: Robert H. Singer, Chair of Committee Gary S. Stein, member of Committee Francis J. Chlapowski, member of Committee Department of Biochemistry Edward G. Fey, member of Committee Steven N. Popoff, member of Committee Dept. of Anatomy and Cell Biology Temple University School of Medicine Philadelphia, PA Sandy C. Marks, Jr. Dissertation Mentor Thomas B. Miller, Dean of the Graduate School of Biomedical Sciences Department/Program of Cell Biology April 1994 ACKNOWLEDGEMENT With the greatest pleasure, I would like to acknowlede those who have supported me in the completion of the work presented in this dissertation. No person is as an island, and it is hrough interactions with others, both colleagues and friends, that one grows in life. Accrdingly, I would like to extend heartelt apreciation to my mentor, Dr. Sandy C. Mark, Jr., for accpting this unseasoned and naive graduate student into his lab and providing me the opprtunity to pursue a research project with personal and professional interests. His generosit and keen insight have been a constant source of inspiration and have allowed me to experience a breadth of opportunities few graduate students enjoy. Sandy s advice, criticism and encouragement have guided the work emboied in this dissertation. I wish to extend thanks to Dr. Victoria Shalhoub for her scientifIC guidance in the isolation and characterization of mRNAs from bone. Her generosity and patience has made the process of Northem hybridization enjoyable. I wish to acknowledge the dilgent work of those "behind-the-scenes , without whom this work would not be complete. I espeially thank Michael Jolie, who performed the histomorphometry necessary for enumerating osteoclasts and mononuclear cells around erupting molars in the rat. The many hours he spent on the Gateway 2000 are greatly appreciated. I would also like to extend thanks to April Mason-Savas for the quality thin sections needed for ultrastructural examination of osteoclasts and "down- to-the-wire" photographic printing. Ukewise, I wish to thank Cindy Richards for an commendable attention to detail in helping me put all of this work together. I would like to express gratitude to the members of Sandy's lab for providing a stimulating research environment, constant supprt, and technical assistance throughout the completion of this thesis. Thank you all for the annual lab field trips, including strawbrr picking, holiday shopping, and the Cape extravaganzas. You have taught me to cherish the personal side of life, that there is more to life than lab work and study. The yearly influx of visiting postdoctoral fellows was rewarding both scientifically and culturally. I especally wish to thank Dr. Tadashi lizuka for his enthusiastic advice during the tooth eruption phase of this thesis. His exprtise in oral pathology faciltated my understanding of tooth development during tooth eruption. I would also like to thank Dr. Kai Sundquist for frank, helpful discussions abut osteoclast biology, the management of clinicl cases in dentistry, and life in general. I am grateful for the frendships I gained with Tadashi and Kai through their time in the lab. I would like to express my deepest thanks to close friends Carole MacKay, Dr. Leslie Wisner-Lynch, and Erik Larson. Their professional deication to and belief in the ongoing work in the lab, together with their wilingness to help others has been inspirational. I shall always remember their supprt and encouragement, which have guided me through the most diffcult endeavors. I would like to express my sincere gratitude to my parents, Martha and Michael Cielinski for believing in me. They never pushed, but instiled in their children the morals and convictions to pursue their dreams, no matter how diffICult. I am grateful. Finally, I would like to share this accmplishment with my wife, Jill. Her love, encouragement, and support have made this endeavor possible. I am fortunate to have in her both wife and best friend. ABSTRACT Osteopetrosis is a metabolic bone disease in mammals characterized by a generalized skeletal scerosis caused by reduced bone resorption. This reduce bone resorption is manifested in afficed animals by abnormal bone shap, reduced or absent marrow cavities, extramedullary hemopoiesis, abnormal mineral homeostasis and absent or delayed tooth eruption. The available osteopetrotic animal mutations have been a constant source of fruitfl investigations concerning the systemic regulation of osteolastogenesis and bone metablism. Tooth eruption, on the other hand, is a loalized manifestation of the timely activation of bone resorption and bone formation on opposite sides of an erupting tooth. Its rate-limiting step is the speed of bone resorption to form the eruption pathway. In this dissertation, we used two osteopetrotic rat mutations, toothless (to and microphthalmia blanc (mi, to investigate the abnormal development of osteoclasts and tooth eruption in mutant rats with an emphasis on the role of systemic and local factors. The significant contributions to this work are listed below. 1. In the toothless rat, a mutation lacking erupted dentition due to severely reduce bone resorption, colony-stimulating factor-1 (CSF-1) promoted tooth eruption but this was delayed compared to normal rats. Eruption was accmpanied by changes in the populations of tartrate-resistant acid phosphatase-positive (TRAP+) mononuclear cells in the dental follicle and TRAP+ osteoclasts on adjacent alveolar bone surfaces. These cell populations were dramatically increased in treated mutants compared to untreated rats, but the timing of their aparance was delayed compared to normallittermates. This lag in the aparance of osteolasts and their precursors correspnded to the delay in eruption of first molars in treated 11 rats. 2. CSF-1 also acclerated the eruption of molars in normal rats. CSF-1 increased the number of TRAP+ mononuclear cells in the dental follcle and TRAP+ osteolasts on adjacent alveolar bone surfaces, but had no effect on the timing of their appearance in normal rats. 3. Our data revealed a differential effect on tooth eruption of the growth factors CSF-1 and epidermal growth factor (EGF). CSF-1 acclerated eruption of molars in normal n ts, but had no effect on incisor eruption. On the other hand, EGF accelerated incisor eruption; but did not affect molar eruption in normal rats. 4. We have describe the mecanism for the transient, mild form of osteopetrosis inherited by mi rats. Mutant animals possess a typical sclerosis at birth, which diminished--but was not resolved--during the first postnatal month. These characteristics are caused by early reductions in osteoast number and function which improve to normal levels by 4 weeks. Osteolast numbers were severely reduced in rats between birth and 2 weeks, but improved to near normal levels by 4 weeks. Neonatal abnormaliies in osteoclast function included reduced staining for the functional enzymes TRAP and TrATPase, decreased levels of mRNA for both TrATPase and CAli, and inabilty to form a well-developed ruffled border. None of these defects were apparent after the first postnatal month. 5. Finally, we have shown that the dental abnormalities caused by the mild, transient form of osteopetrosis in mi rats are limited to incisor defects and delayed eruption of all teeth. Histologic and radiographic examination of mutant incisors revealed that, contrary to the situation in normal rats, the apex of the incisors of rats failed to extend past the first molar region to the third molar. The incisor apex of newbrn mi rats was misshap due to ankylosis of incisor matrices with alveolar bone. This ankylosis was temporary, being resolved by the third postnatal day. The delayed
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