Osteoporosis is a skeletal disorder that affects millions of people worldwide, and is characterized by the accelerated loss of bone mass. Current anti-resorptive drug approaches such as bisphosphonates and salmon calcitonin exhibit severe side effects and very low bioavailability, respectively. In this study, we have designed, synthesized, and performed preliminary tests on a novel conjugate that targets the RANK receptor on bone resorbing cells (osteoclasts) in vitro with one arm, while delivering a specific effector molecule, calcitonin, to osteoclasts with the other arm. First, we successfully generated osteoclasts from precursor RAW 264.7 cells and confirmed that they were functional. We also designed a resorption assay that can be used to test the efficacy of new and existing anti-resorptive drugs. RAW 264.7 cells were then treated with an antibody to RANK to prove that anti-RANK could be used as a targeting mechanism. We then showed that delivery of calcitonin-loaded anti-Calcitonin antibodies onto osteoclasts results in the association of calcitonin onto its receptors on osteoclasts. Finally, we constructed a novel conjugate: calcitonin–Streptavidin–anti-RANK, and showed that it can be used to introduce calcitonin into an osteoclast-like microenvironment.

Bibliography: leaves 141-169. / xix, 170, [63] leaves, [49] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Calcitonin (CT) is a 32 amino acid peptide hormone, known to inhibit osteoclastic bone resorption by direct interaction with cell surface calcitonin receptors (CTR). This study aims to define the intracellular mechanisms by which CT treatment results in decreased cellular proliferation. Results show, for the first time, that the growth regulating actions of CT are receptor isoform specific. In addition, CT inhibition of cellular proliferation occurs by arresting cells in the G2 phase of the cell cycle via a p21 mediated mechanism, which is at least partially activated through the Erk1/2 Map Kinase pathway. / Thesis (Ph.D.)--University of Adelaide, Dept. of Orthopaedics and Trauma, 2000

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 6 uppsatser.

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Thesis--University of Göteborg. / Includes bibliographical references (p. 26-29).

Thesis--University of Göteborg. / Includes bibliographical references (p. 26-29).

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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.