| Summary: | Skeletal shape and mechanical properties define, to a large extent, vertebrate morphology and physical capacities. During development, skeletal morphogenesis results from dynamic communications between chondrocytes, osteoblasts, osteoclasts, and other cellular components of the skeleton. Later in life, skeletal integrity depends on the regulatory cascades that assure the equilibrium between bone formation and resorption. Finally, during aging, skeletal catabolism prevails over anabolism resulting in progressive skeletal degradation. These cellular processes depend on the transcriptional cascades that control cell division and differentiation in each cell type. Most <i>Distal-less</i> (<i>Dlx</i>) homeobox transcription factors are directly involved in determining the proliferation and differentiation of chondrocytes and osteoblasts and, indirectly, of osteoclasts. While the involvement of <i>Dlx</i> genes in the regulation of skeletal formation has been well-analyzed thanks to several mutant mouse models, the role of these genes in the maintenance of bone integrity has been only partially studied. The importance of <i>Dlx</i> genes for adult bone tissues is evidenced by their central role in the regulatory pathways involving <i>Osx/Sp</i>7 and <i>Runx2</i>, the two major master genes of osteogenesis. <i>Dlx</i> genes appear to be involved in several bone pathologies including, for example, osteoporosis. Indeed, at least five large-scale GWAS studies which aimed to detect loci associated with human bone mineral density (BMD) have identified a known <i>DLX5/6</i> regulatory region within chromosome 7q21.3 in proximity of SEM1/FLJ42280/DSS1 coding sequences, suggesting that <i>DLX5/6</i> expression is critical in determining healthy BMD. This review aims to summarize the major findings concerning the involvement of <i>Dlx</i> genes in skeletal development and homeostasis and their involvement in skeletal aging and pathology.
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