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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08212005-230349 |
| Date | 01 September 2005 |
| Creators | Ehrlich, Lori A. |
| Contributors | Andrew Stewart, MD, Richard Steinman, MD PhD, Thomas Smithgall, PhD, Anuradha Ray, PhD, G. David Roodman, MD PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08212005-230349/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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