Dysregulation of Indian hedgehog - parathyroid hormone related protein signalling in cartilaginous neoplasia

grantor: University of TorontoEnchondroma is a benign cartilage-forming tumour of bone that might be caused by dysregulation of growth plate signals. A paracrine feedback loop couples Indian hedgehog (IHH), which stimulates growth plate chondrocyte proliferation, to Parathyroid hormone related protein (PTHrP), which regulates chondrocyte differentiation. Here I show that these two signalling pathways were uncoupled and IHH was dysinhibited in explant cultures of human enchondromas and their malignant counterparts, chondrosarcomas. A heterozygous variant 'Type I PTH'/'PTHrP receptor' ('PTHR1') was discovered in the germline of one patient and as a somatic change in another with enchondromatosis. In this condition, multiple enchondromas may lead to deformity and chondrosarcoma. The variant PTHR1 suppressed Cyclic adenosine monophosphate baseline level in a dominant fashion and abolished Inositol triphosphate accumulation 'in vitro'. Transgenic mice expressing the variant receptor under the regulatory elements of 'Type II' collagen developed enchondromatosis. I show that the transcription factor Gli2 was a positive regulator of Ihh function in the murine growth plate, while Gli3 was a negative regulator. Overexpression of 'Gli2' was found in human enchondromas, and was sufficient to cause enchondromatosis in transgenic mice. A lack of ' Gli3' accelerated another condition of benign chondrocyte neoplasia, synovial chondromatosis. Patched 1 (PTCH1), a Hedghehog receptor, formed a complex with PTHR1, and this complex was required for effective accumulation of PTHR1 second messengers. The variant PTHR1 did not associate with PTCH1, and constitutively activated Hedgehog signalling in a manner that was likely dependent upon suppression of Protein kinase A. Dysregulation of growth plate signals causes certain benign cartilage tumours. Agents that block Hedgehog signalling in particular, might be useful in preventing the deleterious sequelae of enchondromas.Ph.D