Heritable diseases of the skeleton. Part I: Molecular insights into skeletal development-transcription factors and signaling pathways.

The recent identification of the genetic basis of hereditary skeletal disorders is providing important insights into the intricate processes of skeletal formation, growth, and homeostasis. These processes include patterning events during condensation and differentiation of mesenchymal cells to form cartilage precursors of the future bones, the replacement of cartilage by bones through endochondral ossification, the growth of long bones through proliferation and differentiation of chondrocytes in growth plates, and bone formation through differentiation of osteoblasts from mesenchymal cells in areas of intramembranous ossification. Defects in any of these processes can give rise to skeletal abnormalities. Mutations in transcription factors such as HOX and PAX and members of the transforming growth factor-beta superfamily cause disorders associated with abnormal mesenchymal condensation, whereas defects in the transcription factor SOX-9 lead to abnormalities in chondrocyte differentiation. Abnormal growth plate function, resulting in dwarfism, is the consequence of mutations in receptors for fibroblast growth factors and parathyroid hormone-related peptide. Premature closure of cranial sutures in intramembranous ossification is a feature of syndromes due to mutations in fibroblast growth factor receptors.