Osteochondroma is a cartilage capped benign bone tumour, arising at the external surface of bones preformed by endochondral ossification. A small percentage of osteochondromas can progress towards... Show moreOsteochondroma is a cartilage capped benign bone tumour, arising at the external surface of bones preformed by endochondral ossification. A small percentage of osteochondromas can progress towards its malignant counterpart, secondary peripheral chondrosarcoma. About 15% of osteochondromas occur in the context of a rare hereditary syndrome, Multiple Osteochondromas for which two genes have been identified as causative genes, namely EXT1 and EXT2, which have been identified as tumor suppressor genes. However the vast majority of osteochondromas present as solitary lesions. We were able to demonstrate that similar to hereditary osteochondromas EXT1 also acts as a classical tumour suppressor gene in solitary osteochondroma. The EXT genes function as a complex in the biosynthesis of heparin sulphate proteoglycans (HSPGs), large multifunctional macromolecules that are involved in several growth signaling pathways. We showed that the loss of EXT1 and in hereditary cases also EXT2 is accompanied by intracellular accumulation of HSPGs, suggesting a disrupted EXT1/2 complex. The growth signalling pathways known from normal longitudinal bone growth are affected differently in osteochondromas and chondrosarcomas. The IHH signaling functions autonomously in osteochondromas and its activity decreases during malignant transformation and progression of chondrosarcomas, whereas the PTHLH and TFG-_ signaling cascades seem to be re-activated. Show less
