THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
Kent State University / OhioLINK
2017
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-kent1492641831208575 |
|---|---|
| record_format |
oai_dc |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-kent14926418312085752021-08-03T07:01:56Z THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS Moussa, Fouad M. Biomedical Research MOUSSA, FOUAD M., Ph.D., December 2016 BIOMEDICAL SCIENCESTHE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLSDissertation 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. 2017-04-24 English text Kent State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575 http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biomedical Research |
| spellingShingle |
Biomedical Research Moussa, Fouad M. THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS |
| author |
Moussa, Fouad M. |
| author_facet |
Moussa, Fouad M. |
| author_sort |
Moussa, Fouad M. |
| title |
THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS |
| title_short |
THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS |
| title_full |
THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS |
| title_fullStr |
THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS |
| title_full_unstemmed |
THE EPIGENETIC REGULATION OF OSTEOACTIVIN/GPNMB IN BONE CELLS |
| title_sort |
epigenetic regulation of osteoactivin/gpnmb in bone cells |
| publisher |
Kent State University / OhioLINK |
| publishDate |
2017 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=kent1492641831208575 |
| work_keys_str_mv |
AT moussafouadm theepigeneticregulationofosteoactivingpnmbinbonecells AT moussafouadm epigeneticregulationofosteoactivingpnmbinbonecells |
| _version_ |
1719451820022038528 |