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THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS

Moussa, Fouad M
http://orcid.org/0000-0001-7454-7170
http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575

Abstract Details

2017, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
MOUSSA, FOUAD M., Ph.D., December 2016 BIOMEDICAL SCIENCES THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS Dissertation Advisor: Fayez F. Safadi, Ph.D. Osteoporosis is a devastating disease in elderly patients and postmenopausal women. In present day, there are few treatments available on the market but all have limitations and side effects. Therefore, there is a need for new and more effective therapeutic modalities that stimulate bone formation and inhibit bone resorption. Osteoactivin/GPNMB was first discovered in bone by our lab, where we showed its unique role in stimulating osteoblastogenesis and inhibiting osteoclastogenesis, which may lead to net effect of increased bone mass and volume. Although our lab has published on the role of Osteoactivin/GPNMB in osteoblast and osteoclast, but yet, there are no reports on the epigenetic regulation of Osteoactivin/GPNMB in bone cells. In this study, we investigated the posttranscriptional regulation of Osteoactivin/GPNMB by miR-150. Our results showed that Osteoactivin/GPNMB is targeted by miR-150 in osteoblast and osteoclast, and lack of miR-150 enhanced the expression of Osteoactivin/GPNMB in both cell types. Our data revealed that deficiency of miR-150 increased osteoblast differentiation and function, whereas this deficiency lead to decreased osteoclast differentiation and function in vitro. Therefore, we propose that miR-150 is a negative regulator for osteoblast and positive regulator for osteoclast differentiation and function, at least in part, by targeting Osteoactivin/GPNMB. In our next study, we investigated the epigenetic regulation of Osteoactivin/GPNMB through DNA and histone methylation. Our results showed that Osteoactivin/GPNMB gene is highly methylated at early stage of osteoblast differentiation, and its methylation level decreases as cells progress in differentiation. We also showed that Osteoactivin/GPNMB promoter is occupied by H3K27, which is methylated by Ezh2. Our data showed that inhibition of Ezh2 activity enhanced Osteoactivin/GPNMB expression and osteoblast differentiation and function, represented by increased ALP staining and activity, and mineralization. On the other hand, inhibition of Ezh2 had no effect on Osteoactivin/GPNMB-mutated osteoblast. We also showed that inhibiting Ezh2 activity enhanced bone formation in normal mouse calvarial organ culture, whereas no significant effects were shown in Osteoactivin/GPNMB-mutated calvarial organ culture. In conclusion, Osteoactivin/GPNMB expression is posttranscriptionally regulated by miR-150 and epigenetically regulated through DNA and histone methylation. Our observations may give new insights or possibilities for potential therapies to treat osteoporosis or stimulate bone formation in cases of fractures. Future studies may focus on investigating the effects of in vivo use of miR-150 and Ezh2 inhibitors in increasing Osteoactivin/GPNMB expression and bone mass.
Fayez Safadi, Ph.D. (Advisor)
Tariq Haqqi, Ph.D. (Committee Member)
Denise Inman, Ph.D. (Committee Member)
Min-Ho Kim, Ph.D. (Committee Member)
Moses Oyewumi, Ph.D. (Committee Member)
Gail Fraizer, Ph.D. (Committee Member)
191 p.
Biomedical Research

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Citations

  • Moussa, F. M. (2017). THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575

    APA Style (7th edition)

  • Moussa, Fouad. THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS. 2017. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575.

    MLA Style (8th edition)

  • Moussa, Fouad. "THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS." Doctoral dissertation, Kent State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575

    Chicago Manual of Style (17th edition)

kent1492641831208575
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This open access ETD is published by Kent State University and OhioLINK.