The studies presented in this dissertation offer evidence to support the hypothesis that polyphenolic curcuminoids isolated from the plant turmeric (Curcuma longa L.) are bone-protective in metabolic bone disorders characterized by excessive osteoclastic bone resorption. Activation of the critical transcription factor NF-kappaB in osteoclast precursor RAW 264.7 cells and osteoclastogenesis in rat primary bone marrow cell culture were directly inhibited by curcuminoids. Loss of bone mineral density and impaired structural connectivity of the trabecular bone microarchitecture associated with ovariectomy and estrogen deficiency were attenuated by curcuminoids in a rat model of postmenopausal osteoporosis. Additionally, the studies presented in this dissertation offer evidence for bone-protection conferred by curcuminoids by demonstrating for the first time their potent inhibitory effect on breast cancer cell secretion of the osteolytic peptide parathyroid hormone-related protein (PTHrP) via inhibition of Smad-dependent TGF-beta signaling in MDA-MB-231 cells. Finally, curcuminoids inhibited osteolytic lesion formation in a PTHrP-mediated murine model of breast cancer bone metastasis. Taken together, these novel and encouraging findings justify the need for further studies to determine whether curcuminoids may hold promise for the prevention of bone loss and associated complications in resorptive bone diseases in women.
|Advisor:||Funk, Janet L.|
|Commitee:||Going, Scott B., Hoyer, Patricia B., Schroeder, Joyce A.|
|School:||The University of Arizona|
|School Location:||United States -- Arizona|
|Source:||DAI-B 73/08(E), Dissertation Abstracts International|
|Keywords:||Bone resorption, Breast cancer, Curcuminoids, Metastasis, Osteoclast, Postmenopausal osteoporosis|
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