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OSTEOACTIVIN IN SKELETON: CHARACTERIZATION OF OSTEOACTIVIN KNOCKOUT MICE & THERAPEUTIC IMPLICATIONS

Stinnett, Hilary M
http://rave.ohiolink.edu/etdc/view?acc_num=kent1428859108

Abstract Details

2015, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Osteoporosis impacts 55% of the population aged 50 and older, with post-menopausal, thin women of Caucasian descent at the highest risk for developing this disease. As the median age of the population rises, so does the incident of fracture caused by osteoporosis. Currently, only one bone anabolic factor is available on the market, PTH1-34, with a therapeutic window of only 2 years; new novel bone anabolic factors are needed. One protein with the potential for osteoporosis therapy is osteoactivin (OA). Previous studies have demonstrated the role of OA in osteoblast and osteoclast differentiation and function. In this study, we utilized global OA knockout mice to explore the physiological role of OA in bone homeostasis. We also characterized the role of osteoactivin in osteoblasts and osteoclasts by studying OA-/- cells ex vivo. In addition, we tested how the skeleton responded to stress induced by estrogen-deficient osteoporosis model in OA-mutant (D2J), OA knockout, and their respective wildtype controls. Additionally, we investigated the functional role of osteoactivin-derived peptide OA-D. We hypothesized that osteoactivin was critical for postnatal bone growth and development, and that OA-D would be capable of stimulating bone formation and rescuing osteoporotic phenotypes. We demonstrated that the OA-null animals had increased bone mass. Ex vivo analysis of osteoblast differentiation and function revealed defects in mineralization and differentiation. Next, we observed that osteoclast size due to increased fusion of large osteoclasts was significantly increased in the OA-/- animal. However, osteoclast resorption was significantly decreased. Next, OA-D was tested in C57/Blk6 mice for its ability to stimulate bone mass. We showed that OA-D injection in mice resulted in a trending increase in bone mass. Alternative administration of OA-D showed similar results in bone mass. Ovariectomy of OA mutant and OA-/- animals failed to induce significant bone loss as compared to the wildtype. OA-D injection by intravenous administration failed to rescue estrogen deficiency induced bone loss. Taken together, we conclude that osteoactivin is a positive regulator in osteoblastogenesis, and a negative regulator of osteoclastogenesis. Further research is necessary to identify the appropriate signaling pathways that contributed to this phenotype. OA-D has great potential as a novel bone anabolic therapy, however optimization of dose, administration, and frequency is required. This study highlighted the importance of osteoactivin in bone homeostasis.
Fayez Safadi, PhD (Committee Chair)
Werner Geldenhuys, PhD (Committee Member)
Chris Malcuit, PhD (Committee Member)
Moses Oweyumi, PhD (Committee Member)
Walt Horton, PhD (Committee Member)
Srinivasan Vijayaraghavan, PhD (Committee Member)
Biology; Cellular Biology; Pharmacology
osteoactivin, osteoblast, osteoclast, gpnmb, osteoporosis, knockout mouse model, surgical model, ovariectomy

Recommended Citations

Citations

  • Stinnett, H. M. (2015). OSTEOACTIVIN IN SKELETON: CHARACTERIZATION OF OSTEOACTIVIN KNOCKOUT MICE & THERAPEUTIC IMPLICATIONS [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1428859108

    APA Style (7th edition)

  • Stinnett, Hilary. OSTEOACTIVIN IN SKELETON: CHARACTERIZATION OF OSTEOACTIVIN KNOCKOUT MICE & THERAPEUTIC IMPLICATIONS . 2015. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1428859108.

    MLA Style (8th edition)

  • Stinnett, Hilary. "OSTEOACTIVIN IN SKELETON: CHARACTERIZATION OF OSTEOACTIVIN KNOCKOUT MICE & THERAPEUTIC IMPLICATIONS ." Doctoral dissertation, Kent State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1428859108

    Chicago Manual of Style (17th edition)

kent1428859108
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© , some rights reserved.Creative Commons License OSTEOACTIVIN IN SKELETON: CHARACTERIZATION OF OSTEOACTIVIN KNOCKOUT MICE & THERAPEUTIC IMPLICATIONS by Hilary M Stinnett is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Kent State University and OhioLINK.
Release 3.2.12