Enchondromas are benign cartilage tumors and precursors tomalignant chondrosarcomas. Somatic mutations in the isocitratedehydrogenase genes (IDH1 and IDH2) are present in the majorityof these tumor types. How these mutations cause enchondromasis unclear. Here, we identified the spectrum of IDH mutations inhuman enchondromas and chondrosarcomas and studied theireffects in mice. A broad range of mutations was identified, includingthe previously unreported IDH1-R132Q mutation. These mutationsharbored enzymatic activity to catalyze α-ketoglutarate toD-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in oneallele in cells expressing type 2 collagen showed a disorderedgrowth plate, with persistence of type X-expressing chondrocytes.Chondrocyte cell cultures from these animals or controls showedthat there was an increase in proliferation and expression of genescharacteristic of hypertrophic chondrocytes with expression ofIdh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutantknock-in mice (mutant allele expressed in chondrocytes) did notsurvive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutantconditional knock-in mice, in which Cre was induced by tamoxifenafter weaning, developed multiple enchondroma-like lesions.Taken together, these data show that mutant IDH or D-2HG causespersistence of chondrocytes, giving rise to rests of growth-platecells that persist in the bone as enchondromas.
Defense Response in Slash Pine: Chitosan Treatment Alters the Abundance of Specific mRNAs
