No gross skeletal abnormalities. Misplaced chondrocytes near perichondrium in ribs. Loss of columnar organization in proliferating zone. (4). Col2-rtTA-Cre;Ext1 ...
SUPPLEMENTARY INFORMATION
In format provided by Alman et al. (JULY 2010)
Supplementary Information S1 | Mouse models to study the formation of cartilaginous tumours with respect to EXT and growth plate signalling Mus musculus (mouse) Ext1-/-
General phenotype Fail to gastrulate, lack organized mesoderm and extraembryonic tissues. Smaller embryos Resorbed at E8.5 Phenotypically normal, fertile No tumour formation
Skeletal phenotype -
Ext1 GT/ GT (hypomorphic Ext1 mutation)
Survive until E14.5 Embryos are small and appear oedematous Heart defects No tumour formation
No osteochondromas Reduced size Fused vertebrae Shortened limbs Fusion elbow and knee joints
Ext2 -/-
Die at E6.5 Fail to gastrulate Fail to form primitive streak or mesoderm Normal lifespan Fertile
-
Ext1+/-
Ext2 +/-
Col2-rtTA-Cre;Ext1 e2(neo)fl/e2(neo)fl
(Conditional Ext1 knock
Multiple osteochondromas
Growth plate phenotype -
reference (1)
No osteochondromas Mild reduction in humerus and femur bone density
Enlarged proliferative zone Reduced hypertrophic zone Reduction of HS to near 50% Increased range IHH diffusion Expanded proliferating zone Loss of columnar organization in proliferating zone Severely delayed bone formation Delay in hypertrophic differentiation Reduced amounts of HS to near 20% Elevated range IHH signalling -
(1,2) (3)
(4) Ectoptic bone growths of ribs (osteochondroma-like) No gross skeletal abnormalities Multiple osteochondromalike lesions of the long bones
Misplaced chondrocytes near perichondrium in ribs Loss of columnar organization in proliferating zone Columnar organization at the periphery is disturbed
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(4) (5)
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SUPPLEMENTARY INFORMATION
out in chondrocytes) Col2-Gli2 (Gli2 overexpression) Col2-R150CPTHR1 (mutation in the PTHLH receptor activating hedgehog signalling) Col2-Gli2; p53+/-
In format provided by Alman et al. (JULY 2010)
Multiple enchondromas
Multiple enchondromas
Chondrosarcoma
1. Lin, X., et al. Disruption of gastrulation and heparan sulfate biosynthesis in EXT1- deficient mice. Dev Biol 224(2), 299-311 (2000). 2. Hilton, M.J., Gutierrez, L., Martinez, D.A., & Wells, D.E. EXT1 regulates chondrocyte proliferation and differentiation during endochondral bone development. Bone 36(3), 379-386 (2005). 3. Koziel, L., Kunath, M., Kelly, O.G. & Vortkamp, A. Ext1-dependent heparan
Multiple enchondromalike lesions of the long bones Premature Osteoarthritis Multiple enchondromalike lesions of the long bones
Decreased zone of hypertrophy
(6)
Decreased zone of hypertrophy
(6)
Multiple enchondromalike lesions of the long bones, low grade chondrosarcomas, a few soft tissue sarcomas
Increased zone of hypertrophy, decrease apoptosis
(7)
sulfate regulates the range of Ihh signaling during endochondral ossification. Dev. Cell 6, 801-813 (2004). 4. Stickens, D., Zak, B.M., Rougier, N., Esko, J.D., & Werb, Z. Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development 19;132(22), 5055-5068 (2005). 5. Jones, K.B., et al. A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc
NATURE REVIEWS | CANCER
Natl Acad Sci U S A, 107, 2054-2059 (2010). 6. Hopyan, S., et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat. Genet. 30, 306310 (2002). 7. Ho, L., et al. Gli2 and p53 cooperate to regulate IGFBP-3- mediated chondrocyte apoptosis in the progression from benign to malignant cartilage tumors. Cancer Cell 16, 126-136 (2009).
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© 2010 Macmillan Publishers Limited. All rights reserved.
