Hung, Chu-Chih
(2019)
The Role of Magnesium Ions in Osteogenic Signaling Pathways.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Bone fractures are common injuries that typically require surgical treatments involving internal fixation devices to support bone healing. Due to their mechanical strength and biocompatibility, permanent metals such as titanium and stainless steel have become the mainstay for fabrication of implantable devices. However, despite these attributes, traditional non-biodegradable metals are associated with risk for long-term complications which potentially could lead to a second surgery to remove the implants. Magnesium (Mg) is a biodegradable material that degrades naturally in human body providing a revolutionary solution for fabrication of orthopedic implants. In addition, several in vivo studies observed bone healing and new bone formation around the implanted Mg devices. However, the underlying mechanism of how Mg regulates osteogenesis is still unclear. To ensure safe use of Mg-based implants in humans, as well as to better control the osteogenic outcome, it is necessary to understand the corresponding cellular responses and downstream effects that are induced by the corroding Mg. This dissertation provides the rationale to support study of Mg ions (Mg2+) in bone marrow space, and uses multipotent human bone marrow stromal cells (hBMSCs) to demonstrate the activation of Mg2+-induced osteogenic signaling pathways. To begin, osteogenic gene screenings using qPCR arrays were performed to identify potential Mg2+-induced signaling cascades. Our results showed that canonical Wnt/-catenin, HIF/COL10, and PKC signaling pathways were significantly regulated by Mg2+. Mechanistic analyses were performed to investigate cellular responses of these pathways including examination of extracellular ligands, surface receptors, transmembrane channels, intracellular proteins, cytoplasmic kinases, and downstream genes. Our findings showed that unlike a growth factor which binds to a specific cell-surface receptor, elevated extracellular Mg2+ readily transports into cytoplasm and induces multiple intracellular signaling pathways. We further demonstrated the induced osteogenesis in bone marrow space using a rabbit ulna fracture model implanted with Mg fixation plates and screws. Micro-CT and histological analyses showed mineralized deposition surrounding the Mg implants and quantitative results showed a significant increase in new bone volume. The in vitro long-term culture of hBMSCs with Mg2+ also showed increased matrix mineralization supporting the in vivo findings. This dissertation pushes forward the scientific understanding of the mechanisms through which Mg implants promote bone formation and fracture healing. These findings not only will advance the use of Mg-based devices in therapeutic applications, but also provide fundamental support for future studies on related pathways.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
10 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
8 July 2019 |
| Approval Date: |
10 September 2019 |
| Submission Date: |
28 June 2019 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
108 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Magnesium, Bone regeneration, Wnt pathway, Osteogenesis, Human bone marrow stromal cells |
| Date Deposited: |
10 Sep 2019 17:06 |
| Last Modified: |
10 Sep 2019 17:06 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37008 |
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