Hedgehog signaling regulates proliferation in chondrosarcoma: implication for novel therapy

摘要: Chondrosarcomas are the second most frequent malignancy of the skeleton and usually occurs after skeletal maturity. Currently, surgery is the only effective treatment modality. There is no effective chemotherapy or radiotherapy. Enchondromatosis are benign neoplasms consisting of multiple cartilaginous lesions. These tumors arise on the metaphyseal side of the growth plate in bones that undergo endochondral ossification. There is a risk of malignant transformation from enchondroma to chondrosarcoma1. A mutation in a parathyroid hormone receptor (R150C PTHR1) is present in some cases of multiple enchondromatosis. The R150C PTHR1 leads to excessive hedgehog signaling in vitro. Transgenic mice expressing R150C PTHR1 develop enchondromatosis. An over expression of the hedgehog transcription factor, Gli2, also leads to enchondromatosis in mice. The in-vitro data together with the information from these two transgenic mice suggests that over-activation of hedgehog signaling is important in the pathogenesis of enchondromatosis2.Hedgehog signaling pathway is important in regulating the proliferation and differentiation of growth plate chondrocytes. The growth plate, located between the cartilaginous epiphysis and the newly generated bone in the metaphysis, is responsible for longitudinal bone growth. In the growth plate cartilage, Indian hedgehog (IHH) and Parathyroid hormone related protein (PTHrP) are involved in a feedback loop. IHH stimulates chondrocyte proliferation in the growth plate and increases expression of secreted PTHrP. PTHrP in turn regulates chondrocyte differentiation and inhibits the expression of …