Gli2 and p53 Cooperate to Regulate IGFBP-3- Mediated Chondrocyte Apoptosis in the Progression from Benign to Malignant Cartilage Tumors

Ho, Lee Kwang; Stojanovski, Aneta; Whetstone, Heather; Wei, Qing Xia; Mau, Elaine; Wunder, Jay S.; Alman, Benjamin A.

doi:10.1016/j.ccr.2009.05.013

Cited by 79 publications

(56 citation statements)

References 53 publications

(72 reference statements)

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“…This notion is supported by the overall low frequency of genes harboring mutations in chondrosarcomas (33). This finding is consistent with previous data from mice overexpressing the Gli2 transcription factor, which develop enchondroma-like lesions but when crossed with mice deficient in p53, develop chondrosarcomas (34). Indeed, we found reregulation of Hh target genes with expression of the mutant receptor, and the phenotype that we observed was identical to that seen with overexpression of Gli2 in chondrocytes.…”

Section: Discussionsupporting

confidence: 81%

Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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112

118

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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.isocitrate dehydrogenase | cartilage tumor | hedgehog E nchondromas, one of the most common benign tumors occurring in bone, are present in more than 3% of the population (1, 2). They are composed of cells derived from chondrocytes and occur as solitary lesions or multiple lesions in enchondromatosis syndromes (Ollier disease or Maffucci syndrome-in the latter, enchondromas are associated with vascular malformations). Clinical problems caused by enchondromas include pain, fractures, and skeletal deformity. There is a potential for malignant progression to chondrosarcoma that may be greater than 50% in some cases of multiple enchondromatosis (i.e., Maffucci syndrome) (3-7). Many chondrosarcomas are thought to derive from enchondromas, and such sarcomas are termed central chondrosarcomas (3).The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14). Disruption of this feedback loop can result in either skeletal dysplasias with abnormal bone growth or enchondromas; 5% of enchondromas harbor mutation in parathyroid hormone-like hormone receptor (PTHR1), resulting in activation of Hh signaling (6,(10)(11)(12)(13)(14), and expression of a mutant PTHR1 or overexpression of the Hh-regulated transcription factor Gli2 under the Col2a1 promoter causes enchondroma-like cartilage lesions to develop adjacent to the growth-plate ...

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Section: Discussionsupporting

confidence: 81%

Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

112

118

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“…55 In a p53 deficient background, the Gli2 transgenic mice develop larger cartilage lesions associated with the growth plate at 12 months of age. 56 These tumors showed cytological similarities to that of a low grade chondrosarcoma, in which the progression from benign enchondroma was attributed to a significant reduction in chondrocyte apoptosis resulting from the synergistic effects of Gli2 elevation and p53 loss.…”

Section: The Interdependent Ecosystem: Hh and P53 Pathway Interactionsmentioning

confidence: 95%

Protecting the hedgerow: p53 and Hedgehog pathway interactions

Alman²

2010

Cell Cycle

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“…Explant Cultures-Hind limb organ cultures from 16.5-day post-coitum embryos were established as described previously (3,4,13,16). Limbs were placed on a Nucleopore filter inside a well of a 24-well tissue culture plate, with the limb at the liquid/ air interface.…”

Section: Methodsmentioning

confidence: 99%

Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate

Hsu¹,

Zhang²,

Cheng³

et al. 2012

Journal of Biological Chemistry

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Background: Hh and Pthlh signaling pathways play important roles in regulating growth plate chondrocyte differentiation. Results: Pthlh increases Sufu protein levels, and Sufu is required for the effect of Pthlh on chondrocyte differentiation. Conclusion: Pthlh regulates chondrocyte differentiation and Gli activity in a Sufu-dependent manner. Significance: The interaction between Pthlh, PKA, Sufu, and Gli transcriptional activities explains how Pthlh regulates chondrocyte differentiation.

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Gli2 and p53 Cooperate to Regulate IGFBP-3- Mediated Chondrocyte Apoptosis in the Progression from Benign to Malignant Cartilage Tumors

Cited by 79 publications

References 53 publications

Mutant IDH is sufficient to initiate enchondromatosis in mice

Mutant IDH is sufficient to initiate enchondromatosis in mice

Protecting the hedgerow: p53 and Hedgehog pathway interactions

Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate

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