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12 Genetics of Human Skeletal Disease

Bjorn R. Olsen


During the past 25 years, the use of genetic approaches has contributed substantially to the understanding of skeletal development and growth. Identification of mutations responsible for a large number of human osteochondrodysplasias and dysostoses (Mundlos and Olsen 1997a,b) has provided insights into the roles not only of individual genes, but also of entire developmental pathways. The correlation of clinical phenotypes with molecular alterations has allowed analyses of structure-function relationships. Coupled with studies of the phenotypic consequences of gene mutations in inbred mouse strains, and more recently also in zebrafish, such analyses have resulted in deep insights into the genetic mechanisms that underlie skeletal assembly, growth, maintenance, and functions.

The vertebrate skeleton is the product of mesenchymal cells (osteochondroprogenitors of cartilage-forming chondrocytes and bone-forming osteoblasts) derived from cranial neural crest, paraxial mesoderm, and lateral plate mesoderm (Olsen et al. 2000). Bone marrow-derived myeloid cells are the progenitors for bone- and cartilage-resorbing cells, called osteoclasts.

Neural crest cells give rise to the branchial arch derivatives of the craniofacial skeleton, paraxial mesoderm contributes to both the craniofacial and the axial skeleton, and the lateral plate mesoderm supplies progenitor cells for the limb skeleton (Fig. 1). Progenitor cells from these sources migrate into the regions in which future bones are formed, condense into elements of high cellular density, and differentiate into either osteoblasts or chondrocytes. Osteoblastic differentiation, followed by synthesis of bone extracellular matrix, occurs in regions of membranous ossification, such as the calvarium of the skull, the maxilla,...

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