The oncometabolite D-2-hydroxyglutarate induced by mutant IDH1 or -2 blocks
osteoblast differentiation in vitro and in vivo
#MMPMID26046462
Suijker J
; Baelde HJ
; Roelofs H
; Cleton-Jansen AM
; Bovée JV
Oncotarget
2015[Jun]; 6
(17
): 14832-42
PMID26046462
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Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a somatic
mosaic fashion in patients with multiple enchondromas. Enchondromas are benign
cartilaginous tumors arising in the medulla of bone. The mutant IDH1/2 causes
elevated levels of D-2-hydroxyglutarate (D-2-HG). Mesenchymal stem cells (MSC)
are the precursor of the osteoblastic, chondrogenic and adipocytic lineage and we
hypothesized that increased levels of D-2-HG cause multiple enchondromas by
affecting differentiation of MSCs. Bone marrow derived MSCs from different donors
were differentiated towards osteoblastic, chondrogenic and adipocytic lineage in
the presence or absence of 5 mM D-2-HG. Three of four MSCs showed near complete
inhibition of calcification after 3 weeks under osteogenic differentiation
conditions in the presence of D-2-HG, indicating a block in osteogenic
differentiation. Two of four MSCs showed an increase in differentiation towards
the chondrogenic lineage. To evaluate the effect of D-2-HG in vivo we monitored
bone development in zebrafish, which revealed an impaired development of
vertebrate rings in the presence of D-2-HG compared to control conditions
(p-value < 0.0001). Our data indicate that increased levels of D-2-HG promote
chondrogenic over osteogenic differentiation. Thus, mutations in IDH1/2 lead to a
local block in osteogenic differentiation during skeletogenesis causing the
development of benign cartilaginous tumors.
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