PhD student University of British Columbia Vancouver, British Columbia, Canada
Introduction: Osteolytic bone lesions are prevalent in up to 90% of multiple myeloma (MM) patients. However, a lack of reliable, immunocompetent and rapid-onset MM bone lesion models impairs the development of novel treatments. The immunocompetent murine Vk*MYC transplant MM model mimics multiple aspects of human MM. Intravenous injection of Vk*MYC MM cells into C57BL/6 mice frequently results in early mortality due to splenomegaly and this impedes the development of osteolytic bone lesions, limiting their utility as a model. Here, we investigated various factors including cell concentration and cell source in conjunction with intrafemoral injection to enhance our understanding of osteolytic bone lesion development in the Vk*MYC MM mouse model.
Methods: We used male and female C57BL/6 mice aged 6-8 weeks as recipients. Murine Vk*MYC MM cells of varying concentrations (0.1×106 to 1×106 cells/mouse) and origins (splenocytes and bone marrow (BM) cells) were transplanted intrafemorally into C57BL/6 mice. PBS-injected C57BL/6 mice were utilized as a control. MM development was monitored through weekly serum protein electrophoresis (SPEP). The hindlimbs and spines were imaged with X-Ray and µ-CT. In addition, MM cells from the spleen and forearm/hip bones were quantified via flow cytometry.
Results: All mice in this study were successfully engrafted, surviving for 6 to 7 weeks post-injection. Based on the imaging and SPEP results, we observed a direct association between the quantity of injected cells and the severity of bone lesions and tumor burden. Moreover, the cell source (BM cells or splenocytes injected into the femur) played a significant role in the severity of bone lesions. Surprisingly, splenocytes caused more extensive lesions and 25-40% of Vk*MYC cells were present in spleens. In contrast, flow cytometry of BM cells derived from forearms and hip bones showed only 4-10% Vk*MYC cells. Every intrafemorally transplanted mouse developed bone lesions that were enriched in the injected femur (proximal and distal) and occasionally appeared in the tibias and/or non-injected femur, depending on the disease stage. No lesions were detected in the spine of any mice.
Conclusions: We have observed that upon intrafemoral injection of Vk*MYC cells, the disease progression exhibits a sufficiently slow rate, allowing for the development of bone lesions even when a high cell count (1×106) is introduced. Additionally, splenocytes demonstrate a capacity to induce bone lesions similar to those caused by BM cells, even with an increased severity attributed to the heightened disease burden. In conclusion, disease dynamics as well as cell source determine the onset of bone lesions.
