Biochemical and Biophysical Research Communications
Geranylgeranyl transferase type II inhibition prevents myeloma bone disease
Section snippets
Materials and methods
The 5T2MM syngeneic model of multiple myeloma. The 5T2MM murine model of multiple myeloma originated spontaneously in elderly C57BL/KaLwRij mice [16]. 5T2MM cells have been propagated since, in vivo, by the intravenous transfer of diseased bone marrow into young syngeneic mice [17]. Male 6-week-old C57BL/KaLwRijHsd mice were obtained from Harlan CPD (Horst, The Netherlands). 5T2MM cells were isolated from the bone marrow of disease-bearing animals, purified, and injected, via the tail vein,
Inhibiting GGTase II with 3-PEHPC decreases osteoclast numbers in vivo
We first examined the affects of 3-PEHPC on osteoclast number and the bone surface occupied by osteoclasts. TRAP-positive osteoclasts were seen lining the cortico-endosteal bone surfaces of naïve and 5T2MM-bearing mice (Fig. 2A). There was a significant increase in osteoclast surface in 5T2MM-bearing mice when compared to naive mice (p < 0.01) (Fig. 2B). In contrast, 5T2MM-bearing mice treated with either 3-PEHPC or risedronate had a reduction in osteoclast surface compared to 5T2MM-bearing mice
Discussion
Compounds that inhibit enzymes in the mevalonate pathway have been shown to be associated with anti-myeloma effects in vivo[20], [21], [22], [23]. However, it is unclear whether these are direct effects or indirect effects via the inhibition of bone resorption. Less is known about whether downstream inhibitors of this pathway also induce anti-myeloma effects in vivo. Given that myeloma cell survival in vitro requires geranylgeranylated proteins [11] we assessed the role of 3-PEHPC, a specific
Acknowledgments
We thank the Leukaemia Research Fund for supporting this work: O. Gallagher, M. Prideaux, A. Willems and C. Seynaeve for expert technical assistance; and the Alliance for Better Bone Health (Proctor & Gamble and Sanofi-Aventis).
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