Defects of human skeletogenesis--models and mechanisms

Heritable diseases of the skeleton are a highly complex group of genetic disorders. Skeletal morphogenesis involves, in principle, four distinct developmental processes: patterning, organogenesis, growth and homeostasis. Defects in patterning affect the number and shape of bones and will result in dysostosis. Organogenesis involves the formation of bone and cartilage as an organ. Defects in growth plate function lead to abnormal proliferation and/or differentiation of chondrocytes resulting in dwarfism and dysplasia. Bone mass, shape and strength are maintained in equilibrium throughout development and adulthood (homeostasis). Animal studies are providing good correlations between specific embryological events and gene function, and consequently a framework for understanding the fundamental pathways that build and pattern bone. Based on the remarkable conservation of basic developmental mechanisms between animal species, connections to human disorders are frequently possible. As examples for recent advances in our understanding of the processes that underlie skeletal pathology, the molecular basis of a patterning defect, synpolydactyly, and a defect of organogenesis, cleidocranial dysplasia, will be presented and discussed.