The oncometabolite D-2-hydroxyglutarate induced by mutant IDH1 or -2 blocks osteoblast differentiation in vitro and in vivo.

Abstract

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.

• Authors: Johnny Suijker, Hans J Baelde, Helene Roelofs, Anne-Marie Cleton-Jansen, Judith V M G Bovée
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 17 Pg. 14832-42 (Jun 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26046462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glutarates
• alpha-hydroxyglutarate
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Animals
• Bone Development (drug effects)
• Bone and Bones (drug effects, embryology)
• Cell Differentiation (drug effects, physiology)
• Cells, Cultured
• Chondrogenesis (drug effects)
• Chondroma (genetics, metabolism)
• Glutarates (metabolism, pharmacology)
• Humans
• Immunohistochemistry
• Isocitrate Dehydrogenase (genetics, metabolism)
• Mesenchymal Stem Cells (cytology, drug effects, metabolism)
• Mutation
• Osteoblasts (cytology, drug effects, metabolism)
• Osteogenesis (drug effects)
• Zebrafish (embryology)