Defects of human skeletogenesis models and mechanisms

Stefan Mundlos

Universitatsklinikum der Humboldt- 'Universität Berlin, Campus Charité Mitte, Institutfür Medizinische Genetik, Schumannstrasse 20/21, 10117 Berlin, Germany

.Abstract. 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.

2001 The molecular basis of skeletogenesis. Wiley, Chichester (Novartis Foundation Symposium 232)p81-101

Skeletal morphogenesis involves, in principle, four distinct developmental processes: patterning, organogenesis, growth, and homeostasis. Patterning describes functions that play a role in the eventual size, shape (gestalt) and number of individual skeletal elements. Genes effecting patterning are expressed in progenitor cells long before overt skeletogenesis. Accordingly, defects in these genes will not affect the skeleton as a whole but can be expected to result in an altered number and shape of individual skeletal elements. Organogenesis involves the differentiation of progenitor cells into chondrocytes or osteoblasts, and the subsequent formation of bone and cartilage as an organ. All longitudinal growth occurs in the growth plates, highly specialized regions of cartilage in which chondrocytes proliferate and differentiate, and where cartilage is ultimately transformed into bone. Defects in growth plate function result in altered growth rates and consequently in dwarfism. Bone mass, shape and strength are maintained in equilibrium throughout development and adulthood by the compensating forces of bone resorption (osteoclasts) and bone formation (osteoblasts).

The study of genetic diseases of bone offers the unique opportunity to identify new genes that have important roles during skeletal development and/or maintenance. At the same time, the patients' phenotype can give important clues to the possible function of the mutated gene. However, frequently the function of a disease-causing gene cannot be investigated in humans. This is particularly true for developmental genes that act during the first weeks after conception. Model organisms are needed to elucidate the function of these genes. Animal studies are providing a good correlation 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 and vice versa are frequently possible.

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