Abstract
Multiple myeloma (MM), the second-most frequent hematologic malignancy, is caused by the neoplastic expansion of clonal plasma cells. Up to 80% of MM patients develop myeloma bone disease (MMBD), a hallmark of which is the development of osteolytic lesions that can lead to skeletal related events such as fractures, spinal cord compression and bone pain. In the Vk*MYC mouse model of MM, MYC is expressed in germinal center B cells, facilitating the formation of malignant plasma cells and development of major characteristics of MM, including MMBD. However, the extent of skeletal changes and underlying cellular mechanisms in the Vk*MYC model has, to date, not been comprehensively described. Here, we provide such comprehensive characterization of MMBD and the associated structural and cellular changes in the femur of mice inoculated with the Vk*MYC cell line Vk14451. Vk*MYC mice developed significant osteolytic lesions in the femur. Serum analysis revealed a notable decrease in the bone formation marker amino terminal propeptide of type I procollagen (P1NP) (-33.3%, p < 0.01) in Vk*MYC mice compared to naïve control mice, while C-telopeptide of type I collagen (CTX-1) levels remained unchanged. Microcomputed tomography (microCT) analysis demonstrated significant deterioration of the trabecular bone structure in Vk*MYC as compared to naïve control mice, evidenced by reductions in bone volume fraction (-49.2%, P < 0.05), bone surface to bone volume ratio (-22.3%, P < 0.001), trabecular number (-46.3%, P < 0.0001) and connectivity density (-79.5%, P < 0.05), as well as increased trabecular separation (+86.3%, P < 0.0001) and thickness (+20.3%, P < 0.001). Cortical bone analysis indicated increased cortical porosity (+164.5%, P < 0.0001) and decreased thickness (-26.9%, P < 0.001) in the Vk*MYC mice. Histological studies revealed a decrease in osteoblast surface relative to bone surface (-49.7%, P < 0.001) and an increase in osteoclast surface relative to bone surface (+53.9%, P < 0.01). Collectively, our findings indicate significant bone loss and development of MMBD in the Vk*MYC mouse model of MM, driven by uncoupled bone remodeling characterized by decreased osteoblast activity and increased osteoclast burden. These data highlight the relevance of the Vk*MYC 14451 syngeneic model of myeloma in studies aiming to explore MM bone disease in immunocompetent C57Blk6 mice.