Role of DLX Regulatory Proteins in Osteogenesis and Chondrogenesis

Abstract

Bone development is a complex process in which several cell types interact, proliferate, differentiate, and die to give rise to skeletal structures. These processes are highly integrated and require continuous and coordinated regulation by soluble molecular signals and transcription factors to assure harmonious bone development and morphogenesis. In the bone, transcription factors often have multiple functions and control the differentiation of more than one skeletal cellular component. In particular, Distal-less (Dlx) homeobox transcription factors play a central role in regulating the proliferation and differentiation of the three major cell types that constitute bone: chondrocytes, osteoblasts, and osteoclasts. The aim of this review is to summarize what is known about the role of Dlx genes in osteogenesis and to emphasize their role as coordinators at different levels of skeletal development. The elucidation of these unifying roles could improve our understanding not only of bone development but also of adult bone anabolism and catabolism resulting in bone homeostasis and might thus help to further our understanding of the genetic factors responsible for predisposition to multifactorial conditions such as osteoporosis.

Dlx5, a Positive Regulator of Osteoblastogenesis, is Essential for Osteoblast-Osteoclast Coupling

“…[3][4][5] All Dlx genes might play a role in chondrogenesis and/or osteogenesis. 6 In particular, Dlx5 is expressed already at very early stages of bone development 7 and has been proposed to play a central role in the control of osteogenesis. Long bones of Dlx5 Ϫ/Ϫ mutant mice present a narrower hypertrophic zone 8 and a defective trabecular component.…”

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

“…[1][2][3] DLX proteins are important regulators of developmental and differentiation processes, including skeletal development. [4][5][6] A missense mutation in DLX5 leads to split hand and foot malformation 7 and DLX5 and DLX6 are positive transcriptional regulators of osteochondroblastic differentiation. 6 DLX3 is defined as an osteogenic regulator, as human mutations in DLX3 lead to tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia that causes increased bone mineral density (BMD) in intramembranous and endochondral bones.…”

“…[4][5][6] A missense mutation in DLX5 leads to split hand and foot malformation 7 and DLX5 and DLX6 are positive transcriptional regulators of osteochondroblastic differentiation. 6 DLX3 is defined as an osteogenic regulator, as human mutations in DLX3 lead to tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia that causes increased bone mineral density (BMD) in intramembranous and endochondral bones. 8 In vitro, osteocalcin (Ocn), Runx2 9,10 and osteoactivin [9][10][11] are directly regulated by DLX3, and overexpression of DLX3 in osteoprogenitors stimulates transcription of osteogenic markers.…”

Dlx genes and the maintenance of bone homeostasis and skeletal integrity

“…RNA-Seq analysis of Dlx3 OCN-cKO metaphysis shows upregulation of transcription factors essential for osteoblastogenesis, including Runx2, 16 its downstream osteoblast-specific target Sp7 17 and Dlx5/Dlx6, two positive regulators of chondrocyte and osteoblast differentiation (see Figure 1). 8,9,18,19 The fact that Dlx3 plays an important role in regulating osteoblast activity is further supported by the analysis of Dlx3-deleted bone marrow stroma cells (BMSCs), which also shows increased osteoblast differentiation and bone-forming activity associated with increased gene expression of Runx2 and Dlx5. The notion that DLX3 acts as a negative regulator of osteoblastogenesis by reducing Runx2, Sp7, Dlx5 and Dlx6 gene expression is further supported by ChIP analysis on BMSCs, which shows that DLX3 binds to the promoters of Sp7, Dlx5 and Dlx6 and Runx2, directly modulating their activity (see also Hassan et al 12 ).…”

“…7 Dlx transcription factors my well play different and synergic roles in the control of chondrogenesis and/or osteogenesis. 8,9 In particular, mutations in DLX3 result in Tricho-DentoOsseous syndrome, an autosomal dominant ectodermal dysplasia characterized by curly kinky hair, enamel hypoplasia, taurodontism and increased bone mineral density (BMD) in intramembranous and endochondral bones. 10 The importance of DLX3 in bone is also supported by its capacity to regulate directly in vitro critical determinants of bone differentiation such as osteocalcin (Ocn), Runx2 and osteoactivin, [11][12][13] and by the observation that overexpression of DLX3 in osteoprogenitors stimulates transcription of osteogenic markers.…”