Far from serving as an inert skeletal scaffold, bone is a dynamic tissue that cycles through tightly coordinated cycles of developmental growth and regeneration. Bone growth, which determines the overall growth of vertebrates, is well-characterized histologically and increasingly understood at the molecular level. In recent years traditional positional cloning applied to diseases of simple Mendelian inheritance have revealed genes important in the proper formation of bone. Functional studies of these genes, aided considerably by insights provided by studies of homologous genes in animal models and other organisms, have led to significant advances in our understanding of the pathways of mammalian bone morphogenesis. One such disorder, hereditary multiple exostoses, is caused by members of the EXT tumor suppressor gene family. Progress in the molecular dissection of this disorder, with emphasis on important genomic techniques and strategies, is reviewed herein. We are now challenged to reconstruct the biochemical pathway of chondrogenesis/osteogenesis defined by the EXT genes as a step toward therapeutic control of bone growth and malignancy.
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