Page 130 - Haematologica August 2018

J. Muller et al. Discussion
In this preclinical study, we demonstrated that MELK inhibitor OTSSP167 is a promising novel therapeutic agent for MMBD since OTSSP167 treatment blocked osteoclast activity and stimulated osteoblast activity in vitro, and completely prevented the development of
MMBD in MM-bearing mice.
Consistent with an osteoclast stimulating activity of fac-
tors downstream of MELK, MELK mRNA levels increased during osteoclastogenesis. In addition, we found signifi- cant mRNA changes in EZH2 and the negative regulator IRF8 known to influence the crucial differentiation factor NFATC1 which was found to be upregulated during osteo-
A
B
C
Figure 6. OTSSP167 decreases osteoclast activity and restores osteoblast activity in multiple
DEFG
which
A) Representative images of TRAP- stained distal femur sections of naive, vehicle- and OTSSP167- treated mice from the 7.5
myeloma-bearing mice.
mg/kg/2d cohort,
showed no effect on MM tumor load. 40X amplifications are shown in the inserts. B) Representative images of tolui- dine blue-stained distal femur sections from the same cohort. C) Representative images of Masson’s trichrome stained dis- tal femur sections from the same cohort. D) Quantification of osteoclast surface (Oc.S/BS). E) Quantification of osteoblast surface (Ob.S/BS). F) Quantification of osteoid sur- face (OS/BS). G) Quantification of osteoid thickness (O.Th). All data are represented as mean +/- standard error. *:P<0.05, **:P<0.01, ***:P<0.001.
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