Myeloma-osteoclast interactions as a therapeutic target for multiple myeloma bone disease

<p>Multiple myeloma (MM) is a cancer of terminally differentiated B lymphocytes, also known as plasma cells, which are cells specialized in generating antibodies. MM is responsible for 35,000 diagnoses and 13,000 deaths in the US annually. While both malignant and non-malignant plasma cells specifically migrate to the bone marrow, myeloma is often accompanied by osteodegenerative disease, which is characterized by an imbalance of bone resorption. Bone disease in multiple myeloma is driven by the dysregulated signaling of myeloma cells and the increased abundance of these cells in the bone marrow. Osteoclasts are bone-resorbing cells formed from the fusion of macrophages in a process known as osteoclastogenesis. Herein, we hypothesized that multiple myeloma cells promote osteoclastogenesis through direct mechanisms by secreting RANKL, the fundamental growth factor of osteoclasts, or through the Notch signaling pathway. Additionally, we hypothesized that multiple myeloma cells indirectly promote osteoclastogenesis by re-educating the tumor stroma to increase expression of RANKL. Using in vitro models, we investigated the influences of multiple myeloma on the differentiation of osteoclasts and discovered divergence in the effect of the human multiple myeloma cell line, MM.1S, on RAW.264.7-derived osteoclasts and primary-derived osteoclasts showing enhancement on the former and inhibition on the latter. Moreover, using a novel assay to detect soluble TRAP, we discovered that the myeloma cell lines MM.1S and RPMI-8226 influence osteoclastogenesis in primary cells differentially. Interestingly, MM.1S was shown to be inhibitory, whereas RPMI-8226 was shown to be stimulatory on committed osteoclast precursors, whereas both were shown to be inhibitory on uncommitted osteoclast precursors. The results of this work further clarify experimental models and the biology of multiple myeloma bone disease, informing precision medicine strategies to ameliorate this disease sequelae.</p>

Name thesis:degree_name

Master of Science (MS) in Biology

Level thesis:degree_level

Thesis: EWU Only

Discipline thesis:degree_discipline

Biology

Year

2025

Author dc:creator

• Roosma, Justin

• Medical Cell Biology
• Musculoskeletal Diseases

Statement dc:rights

• Access perpetually restricted to EWU users with an active EWU NetID

Repository record dc:identifier

https://dc.ewu.edu/theses/981

OAI identifier oai:identifier

oai:dc.ewu.edu:theses-1980