Abstract
Simple SummaryMultiple myeloma is a plasma cell cancer involving bone destruction and is considered an incurable disease despite significant improvements in therapeutic strategies. During myeloma progression, over 90% of patients develop a bone disease that causes patient injury and death. There are limited animal models available to demonstrate multiple myeloma bone disease (MMBD). The current study identifies and validates the newly developed MMBD models with uniformity of tumor burden and severe bone lesions. This model will help study the biology of MMBD and serve as a valuable tool for screening therapeutic candidates by monitoring their response to disease progression.Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM tumorigenesis. However, these models demonstrate little or no evidence of MMBD. We try to establish the MMBD model with severe bone lesions and easily accessible MM progression. 1 × 106 luciferase-expressing 5TGM1 cells were injected into 8–12 week-old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was assessed weekly via in vivo bioluminescence (BL) imaging using IVIS-200. The spine and femur/tibia were extracted and scanned by the micro-computer tomography for bone histo-morphometric analyses at the postmortem. The median survivals were 56 days in NSG while 44.5 days in C57BL/KaLwRij agreed with the BL imaging results. Histomorphic and DEXA analyses demonstrated that NSG mice have severe bone resorption that occurred at the lumbar spine but no significance at the femur compared to C57BL/KaLwRij mice. Based on these, we conclude that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than the C57BL/KaLwRij model.
Highlights
Multiple myeloma (MM) is the second most common hematological threat in the USA, characterized by the accumulation of terminally differentiated monoclonal plasma cells (PCs) in the bone marrow (BM) [1,2]
We found the first signs of MM engraftment and growth at the second week of post-injection in non-obese diabetic (NOD) severe combined immunodeficient (SCID) gamma mouse (NSG) mice compared to the fourth week in C57BL/KaLwRij mice demonstrated by a focal signal on BL Image analyses (Figure 1A)
Engraftments of 5TGM1-Luc cells via tail vein in both C57BL/KaLwRij mice and NSG mice resulted in MM progression with typical MM phenotypes
Summary
Multiple myeloma (MM) is the second most common hematological threat in the USA, characterized by the accumulation of terminally differentiated monoclonal plasma cells (PCs) in the bone marrow (BM) [1,2]. MM is characterized by hypercalcemia, renal failure, anemia, and lytic bone lesions. MMBD develops when MM cells disrupt the balance of bone absorption and formation, resulting in activation of osteolytic devastation [8]. MM progression and osteolytic lesion development are highly linked, demonstrating the interaction of myeloma cells with the bone marrow microenvironment. A number of factors, including Receptor Activator of NF-κB (RANK), RANK ligand, osteoprotegerin, play roles in osteolytic lesions and MM progression. Some of these factors are produced from various immune cells. These findings suggest that crosstalk between the immune system and bone cells may affect cancer growth [10]
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