Ehrlich, Lori A.
(2005)
IL-3-Mediated Osteoblast Inhibition in Multiple Myeloma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Multiple myeloma is a plasma cell malignancy that localizes to the bone. It is diagnosed in 15,000 new patients per year, making it the second most common hematologic malignancy. The major source of morbidity in these patients is due to bone destruction induced by the myeloma cells leading to severe bone pain and pathologic fractures. Bone destruction in myeloma is mediated by an increase in osteoclast activity, the cells that normally resorb bone, with a concomitant decrease in osteoblast number and function, the cells that normally rebuild bone. The cause of the decrease in osteoblasts is not well understood. Interleukin-3 (IL-3) is upregulated in myeloma compared to normal controls and can mediate osteoclast activation in myeloma. This dissertation investigates the potential role of IL-3 as an osteoblast inhibitor in myeloma. First, IL-3 blocked osteoblast differentiation in a primary murine osteoblast culture system in a dose-dependant manner. Importantly, IL-3-mediated osteoblast inhibition occurred at IL-3 levels present in bone marrow samples from patients with myeloma. IL-3 did not inhibit osteoblast differentiation in cell lines, indicating that the IL-3 effects were not direct. Conversely, IL-3 caused proliferation in CD45+ hematopoietic cells present in the primary murine cultures, and depletion of CD45+ cells from these cultures resulted in a loss of IL-3 inhibition of osteoblast differentiation. Reconstitution of cultures with CD45+ cells resulted in restoration of the ability of IL-3 to inhibit osteoblasts. These CD45+ cells were shown to be CD11b+ and in the monocyte/macrophage lineage. Further studies were conducted into the mechanism of IL-3-mediated osteoblast inhibition. Cell-to-cell contact was required between osteoblasts and CD45+ hematopoietic cells, and separation of the cell population by transwell cultures abolished IL-3 inhibition of osteoblasts. Transcript levels of several integrins expressed on osteoblasts were not increased by treatment with IL-3, indicating that increased binding of CD45+ cells to osteoblasts is not the mechanism required for osteoblast inhibition. Contact between CD45+ cells and osteoblasts could result in increased expression of a juxtacrine factor that mediates IL-3 inhibition of osteoblasts. In myeloma, IL-3 can mediate proliferation of malignant cells, stimulation of osteoclast activity, and inhibition of osteoblast activity, which ultimately leads to exacerbation of lytic lesions in these patients. Thus, IL-3 is a potential target for myeloma therapy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Roodman, G. David | | | | | Committee Member | Stewart, Andrew | | | | | Committee Member | Ray, Anuradha | | | | | Committee Member | Steinman, Richard | | | | | Committee Member | Smithgall, Thomas | | | |
|
| Date: |
1 September 2005 |
| Date Type: |
Completion |
| Defense Date: |
22 July 2005 |
| Approval Date: |
1 September 2005 |
| Submission Date: |
21 August 2005 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Biochemistry and Molecular Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
alkaline phosphatase; CD45; Interleukin-3; multiple myeloma; osteoblast |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08212005-230349/, etd-08212005-230349 |
| Date Deposited: |
10 Nov 2011 20:00 |
| Last Modified: |
15 Nov 2016 13:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9222 |
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