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.
Highlights
Enchondroma is a benign cartilage forming tumor within the medullary cavity of the bone [1, 2]
Mesenchymal stem cells (MSC) that were pushed towards osteogenic differentiation in the presence of 5 mM D-2-HG, as a surrogate for isocitrate dehydrogenase 1 (IDH1) or -2 mutation, showed impaired calcification after three weeks as compared to MSCs pushed towards osteogenic differentiation in the absence of D-2-HG
We here demonstrate that elevated levels of D-2-HG block osteogenic differentiation and variably promote chondrogenic differentiation of mesenchymal stem cells
Summary
Enchondroma is a benign cartilage forming tumor within the medullary cavity of the bone [1, 2]. Enchondromas can occur as solitary lesions, of which the exact incidence is unknown as they are often detected when radiographs are made for other reasons. Multiple enchondromas are seen in patients with the rare enchondromatosis syndrome. Different subtypes of enchondromatosis are distinguished, of which the most common ones are Ollier disease and Maffucci syndrome, the latter distinguished by multiple spindle cell hemangiomas in addition to enchondromas [2, 3]. Up to 87% of solitary or multiple enchondromas harbor mutations in IDH1 or IDH2 [4,5,6] We and others have shown that both these non-hereditary syndromes are caused by somatic mosaic heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) genes [4,5,6,7].
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