Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM). Chondrocyte__matrix interactions compensate the lack of cell__cell contact and are modulated by... Show moreChondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM). Chondrocyte__matrix interactions compensate the lack of cell__cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short- and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell__matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the microenvironment is the site of the initiating processes that ultimately lead to cancer. Show less
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
