Sp7 Action in the Skeleton: Its Mode of Action, Functions, and Relevance to Skeletal Diseases

Abstract

Osteoblast differentiation is a tightly regulated process in which key transcription factors (TFs) and their target genes constitute gene regulatory networks (GRNs) under the control of osteogenic signaling pathways. Among these TFs, Sp7 works as an osteoblast determinant critical for osteoblast differentiation. Following the identification of Sp7 and a large number of its functional studies, recent genome-scale analyses have made a major contribution to the identification of a “non-canonical” mode of Sp7 action as well as “canonical” ones. The analyses have not only confirmed known Sp7 targets but have also uncovered its additional targets and upstream factors. In addition, biochemical analyses have demonstrated that Sp7 actions are regulated by chemical modifications and protein–protein interaction with other transcriptional regulators. Sp7 is also involved in chondrocyte differentiation and osteocyte biology as well as postnatal bone metabolism. The critical role of SP7 in the skeleton is supported by its relevance to human skeletal diseases. This review aims to overview the Sp7 actions in skeletal development and maintenance, particularly focusing on recent advances in our understanding of how Sp7 functions in the skeleton under physiological and pathological conditions.

Building model prototypes from time-course data

“…These wiring diagrams present gene-by-gene interactions for the given gene expression data set. For the control case, Wnt5a represents a key node in the network; this Wnt signaling ligand is predicted to activate ligands that function in BMP ( Bmp2 ), FGF ( Fgf9 ), and TGFβ ( Inhbb ) pathways, and transcriptional regulation of bone formation (Sp7) [7], consistent with Wnt signaling playing a central, integrative role in regeneration [26] (Figure 5 a). Additionally, for the control case, we note that the well-established inhibitory effect of Dusp6 on FGF signaling is captured by this wiring diagram [11], and it also implicates Wnt5a as an inhibitor of Areg during regeneration.…”

Could BMPs Therapy Be Improved if BMPs Were Used in Composition Acting during Bone Formation in Endochondral Ossification?

“…In the first step, osteogenic transcriptional factors in MSCs are activated. They include RUNX2 [ 31 ], Sp7 [ 32 ] and DLX5 [ 33 ]. One of the pathways activated by BMPs is connected with Indian hedgehog homolog (IHH) signalling activation, which also stimulates osteogenic transcriptional factors [ 34 ].…”

“…These pre-osteoblasts express osteogenic genes encoding for alkaline phosphatase, collagen1α1 chain (COL1A1), osteopontin, bone sialoprotein II (BSP II) and osteocalcin and differentiate into osteoblasts and osteocytes [ 11 ]. RUNX2 and Sp7 are recognized as essential for the differentiation of osteoblast; their deletion leads to a lack of osteoblasts during both intramembranous and endochondral bone formation [ 32 ]. RUNX2 and Sp7 are responsible for the upregulation of the transcription of numerous osteoblast-related genes.…”

“…RUNX2 causes the expression of COL1A1, OPN, OCN and IBSP (integrin binding sialoprotein) [ 4 ]. Sp7 upregulates the expression of collagens (COL1A1, COL5A1, COL5A3), VEGF, fibromodulin (Fmod), matrix metalloproteinase 9 and 13 (MMP9 and 13); pyrophosphatase/phosphodiesterase 1 (ENPP1), integrin binding sialoprotein (IBSP), sclerostin, osteocalcin, connexin 43 (Cx43) or zinc transporter 1 (ZIP1) [ 32 ]. Acetylation of Sp7 increases its binding to the promoters of genes for ALP, BSP, COL1A1 and osteocalcin, demonstrating that Sp7 acetylation is important for the differentiation of osteoblasts [ 33 ].…”

DLX Genes in the Development and Maintenance of the Vertebrate Skeleton: Implications for Human Pathologies

“…Indeed, targeted inactivation of either Runx2 or Sp7 in the mouse results in complete absence of bone formation due to the lack of osteoblast maturation [ 2 , 3 , 4 , 5 ]. Mutation of either of these two genes in humans results in abnormal bone formation [ 6 , 7 ]. During osteoblast differentiation, mesenchymal progenitors first get committed to the osteoblastic lineage through the activation of Runx2 , then the coactivation of Sp7 defines the transition to osteoblast precursors and finally to mature osteoblasts.…”