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Fatima A Dissertation.pdf (10.75 MB)

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OSTEOACTIVIN PLAYS A NOVEL ROLE IN AUTOPHAGY-MEDIATED BONE HOMEOSTASIS

Jaber, Fatima A
http://rave.ohiolink.edu/etdc/view?acc_num=kent1523662960163492

Abstract Details

2018, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Osteoprosis is a disease affecting most the population all over the world. There are some medications to treat this disease but with side effects. For example, bisphosphonates therapy has side effects including osteonecrosis. Therefore, it is important to discover new medications that increase bone formation and decrease bone resorption. Osteoactivin was discovered in an osteopetrotic mutant rat model. Our lab found that osteoactivin acts as anabolic factor to stimulate bone formation by osteoblasts. Autophagy is a catabolic process that allows cells to eliminate unwanted material. Autophagy related proteins have shown to be important for bone cells. Loss of autophagy could lead to dysfunction in bone homeostasis. In this study, we used the autophagy mTOR-independent and dependent pathways to determine its effects on osteoblast differentiation in vitro ex-vivo, and in vivo. First, we treated mesenchymal stem cells (MSCs) and osteoblast with Trehalose (TH) and Rapamycin (R) in culture, and found an increase in osteoblast differentiation and function determined by alkaline phosphatase (ALP) staining, activity, mineralization, and upregulation of osteoblast related gene expression. We found that treatment with TH and R stimulates osteoblast differentiation. Furthermore, we determined that treatments with TH causes induction of autophagosome formation associated with creating of double membrane of autophagic vacuoles in MC3T3-E1 osteoblast-like cells. Next, we wanted to determine if autophagy is important for osteoactivin mediated signaling in osteoblast. Our results have shown that osteoactivin co-localizes with microtubule-associated protein light chain 3II (LC3II), the main marker for autophagosome formation. Furthermore, we found that treatment with TH and R caused new bone formation in neonatal calvarial organ cultures from DBA/2J GPNMB+ and DBA/2J mice. Lastly, we found that osteoactivin enhanced osteoblast differentiation through the autophagy signaling pathway. In the next study, we wanted to determine the role of osteoactivin on osteoclast differentiation and function by mTOR-independent and dependent pathways. Our results revealed that osteoactivin inhibits osteoclast differentiation and size through mTOR-independent pathway but increases osteoclast function by the mTOR-dependent pathway in vitro study by TRAP staining and activity. While in vivo study showed that both autophagy pathways (mTOR-independent and dependent) causes increased osteoclast differentiation and bone resorption by TRAP staining and µCT. Taken together, we believe that the osteoactivin and mTOR-dependent pathway rapamycin interact with each other to increase osteoblast differentiation, bone formation and osteoclast mediated resorption. However, mTOR-independent pathway by TH causes increased osteoblast differentiation, bone formation, and osteoclast differentiation.
Safadi Fayez, F (Advisor)
300 p.
Biomedical Research; Health Sciences; Molecular Biology
OA; OB; OC; mTOR

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Citations

  • Jaber, F. A. (2018). OSTEOACTIVIN PLAYS A NOVEL ROLE IN AUTOPHAGY-MEDIATED BONE HOMEOSTASIS [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1523662960163492

    APA Style (7th edition)

  • Jaber, Fatima. OSTEOACTIVIN PLAYS A NOVEL ROLE IN AUTOPHAGY-MEDIATED BONE HOMEOSTASIS. 2018. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1523662960163492.

    MLA Style (8th edition)

  • Jaber, Fatima. "OSTEOACTIVIN PLAYS A NOVEL ROLE IN AUTOPHAGY-MEDIATED BONE HOMEOSTASIS." Doctoral dissertation, Kent State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1523662960163492

    Chicago Manual of Style (17th edition)

kent1523662960163492
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This open access ETD is published by Kent State University and OhioLINK.