Mutant IDH is sufficient to initiate enchondromatosis in mice.
Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Makoto
M
Hirata
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
Masato
M
Sasaki
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
Rob A
RA
Cairns
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
Satoshi
S
Inoue
Department of Orthopedic Surgery, Duke University, Durham, NC 27710;
Vijitha
V
Puviindran
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
Wanda Y
WY
Li
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
Bryan E
BE
Snow
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1;
Lisa D
LD
Jones
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Qingxia
Q
Wei
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Shingo
S
Sato
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Yuning J
YJ
Tang
Department of Orthopedic Surgery, Duke University, Durham, NC 27710;
Puviindran
P
Nadesan
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Jason
J
Rockel
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Heather
H
Whetstone
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Raymond
R
Poon
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4;
Angela
A
Weng
Agios Pharmaceuticals, Cambridge, MA 02139;
Stefan
S
Gross
Agios Pharmaceuticals, Cambridge, MA 02139;
Kimberly
K
Straley
Agios Pharmaceuticals, Cambridge, MA 02139;
Camelia
C
Gliser
Chempartner, Shanghai 201203, China; and.
Yingxia
Y
Xu
Department of Orthopedic Surgery, Mount Sinai Hospital, Toronto, ON, Canada, M5G 1X5.
Jay
J
Wunder
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada, M5G 2C1; tmak@uhnres.utoronto.ca benjamin.alman@sickkids.ca.
Tak W
TW
Mak
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada, M5G 0A4; Department of Orthopedic Surgery, Duke University, Durham, NC 27710; tmak@uhnres.utoronto.ca benjamin.alman@sickkids.ca.
Benjamin A
BA
Alman
D019943:Amino Acid Substitution; D000818:Animals; D019902:Chondrocytes / Q000201:enzymology / Q000473:pathology; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D004687:Enchondromatosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D005977:Glutarates / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense
D024043:Collagen Type II; D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase
cartilage tumor; hedgehog; isocitrate dehydrogenase