Altered bone microarchitecture and gene expression profile due to calcium deficiency in a mouse model of myeloma

It is not clear why patients with an indolent form of multiple myeloma (MM) develop into an aggressive form with poor prognostic. We investigated the effect of a dietary calcium deficiency on tumor growth, osteolysis and gene expression in the 5T2MM murine model. Two groups of C57BL/KaLwRij mice received 5T2MM cells and started a diet with normal (0.8%; "normal-Ca-MM") or low calcium content (0.05%; "low-Ca-MM"). Two control groups (without 5T2MM cells) received either a normal or low calcium diet (normal-Ca and low-Ca groups). Tumor growth, osteolysis and marrow gene expression of the Wnt pathway, RANKL and MIP-1 alpha were monitored at 6, 8 and 10 weeks (w) after cell injection. In low-Ca mice, serum level of PTH was higher after 10 w; microCT showed trabecular bone loss and decrease of cortical thickness at the tibia. A higher M-protein level was evidenced at 10 w and 4 mice developed paraplegia at 8/9 win low-Ca-MM group only. Numerous cortical perforations of the tibia were observed in MM groups with a marked decrease in cortical thickness in low-Ca-MM. At 6 w, osteoclast number from the endosteum was significantly higher in low-Ca-MM compared to normal-Ca MM. This observation was not found at 8 and 10 w. MicroCT of the lumbar vertebrae showed dramatic bone destruction in the low-Ca-MM group. qPCR revealed no difference in RANKL expression whereas differences were obtained in the expression of Lrp5/Lrp6 and MIP-1 alpha from 6 w. A low calcium diet induced higher bone destruction in the tibia and vertebra associated with an earlier decrease in bone formation level and a higher increase in bone resorption level at early time in the MM development. (C) 2017 Elsevier Ltd. All rights reserved.