title: 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.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johnny
authors.initials: J
authors.lastname: Suijker
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: Department of Immuno-Haematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Helene
authors.initials: H
authors.lastname: Roelofs
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects; D002812:Chondroma / Q000235:genetics / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Pathology Section; enchondroma; isocitrate dehydrogenase; maffucci syndrome; mesenchymal stem cells; ollier disease