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Endochondral Ossification

GLI2 and P53 Cooperate to Regulate IGFBP-3 Mediated Chondrocyte Apoptosis in the Progression From Benign to Malignant Cartilage Tumours. Louisa Ho, Aneta Stojanovski, Heather Whetstone, Qingxia Wei, Elaine Mau, Benjamin Alman, Jay Wunder The Hospital for Sick Children, Toronto, ON Canada

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Endochondral Ossification

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  1. GLI2 and P53 Cooperate to Regulate IGFBP-3 Mediated Chondrocyte Apoptosis in the Progression From Benign to Malignant Cartilage Tumours Louisa Ho, Aneta Stojanovski, Heather Whetstone, Qingxia Wei, Elaine Mau, Benjamin Alman, Jay Wunder The Hospital for Sick Children, Toronto, ON Canada CTOS -November 14, 2008

  2. Endochondral Ossification Articular chondrocytes Growth plate chondrocytes epiphysis

  3. Growth Plate Chondrocyte Differentiation Periarticular Perichondrium PTHrP Resting Proliferation Ihh Prehypertrophy Hypertrophy Apoptosis

  4. Sufu Gli GliR GliAct Hedgehog Hedgehog Signalling Pathway No ligand With Hh ligand Smo PKA, CI, GSK3β Ptc Ptc Smo Ptc, Gli1, IGF2

  5. Enchondromas are common benign cartilaginous tumors of bone Arise on the metaphyseal side of the growth plate Solitary or multifocal disease May cause pain, skeletal deformity, bony weakness leading to pathologic fracture Enchondromatosis syndromes show a higher risk (32%) of malignant transformation to chondrosarcoma Treatment is usually limited to surgical excision, given its resistance to chemotherapy Mice in which Gli2 is overexpressed within the growth plate develop ECA-like lesions (Hopyan, 2002) Cartilage Tumours

  6. CSA ECA ? Research Questions Hypothesis: Multiple genetic events are involved in the progression of enchondroma to chondrosarcoma • What are the mechanisms by which benign tumors become more aggressive?

  7. Tg(Gli2;ColIIA1) p53 +/- Additional genetic events: P53 tumour suppressor

  8. Changes in the embryonic growth plate • Phenotypic differences more apparent during embryonic development • Proliferation • Differentiation • Apoptosis • Ossification Gli2;P53-/- Gli2OE P53-/- WT

  9. Changes in the embryonic growth plate Differentiation Apoptosis E C D A B

  10. Gli transcription factors directly regulate IGFBP-3 expression A B IGFBP-3 D C

  11. IGFBP-3 promoter assay Gli consensus binding site 5`-GACCACCAG-3` Mutated binding site 5`-GACGAGGAG-3`

  12. IGFBP-3 SHH IGFBP-3+SHH Limb Explants – Changes in Apoptosis WT p53-/- Gli2;p53-/- + Shh IGFBP-3 No Tx +IGFBP-3 +Shh

  13. Human Chondrosarcoma and IGFBP-3 D Fold change IGFBP-3

  14. Model under investigation Periarticular Perichondrium PTHrP Resting Proliferation IGFBP-3 p53 Gli Ihh Prehypertrophy Hypertrophy Apoptosis Overall our data suggests an interaction between the Hh/Gli and p53 signaling pathways in growth plate development and maintenance, in which its combined deregulation contributes to the transformation of benign cartilage neoplasia.

  15. Possible Treatment targets P53 deficiency X X IGF signaling Hh signaling No Tumor Benign Malignant

  16. Acknowledgements • Dr. Jay Wunder • Dr. Cohick • Committee members • Dr. EldadZachsenhaus • Dr. Rita Kandel • Alman lab members • Aneta Stojanovski • Heather Whetstone • Elaine Mau • Qing Xia Wei

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