Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression
30 Sep 2005-Journal of Biological Chemistry (American Society for Biochemistry and Molecular Biology)-Vol. 280, Iss: 39, pp 33132-33140
TL;DR: It is proposed that WNT/TCF1 signaling, like bone morphogenetic protein/transforming growth factor-β signaling, activates Runx2 gene expression in mesenchymal cells for the control of osteoblast differentiation and skeletal development.
About: This article is published in Journal of Biological Chemistry.The article was published on 2005-09-30 and is currently open access. It has received 1069 citations till now. The article focuses on the topics: LRP6 & LRP5.
Citations
More filters
Cornell University1, University of Porto2, Imperial College London3, National Institutes of Health4, Memorial Sloan Kettering Cancer Center5, Princeton University6, Lawrence Berkeley National Laboratory7, Garvan Institute of Medical Research8, Stanford University9, University of Copenhagen10, Fred Hutchinson Cancer Research Center11
TL;DR: This Review summarizes the main processes and new mechanisms involved in the formation of the pre-metastatic niche and describes the main mechanisms used to modify organs of future metastasis.
Abstract: It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.
1,134 citations
TL;DR: This work has revealed novel roles for mediators such as GADD45β, transcription factors of the Dlx, bHLH, leucine zipper, and AP‐1 families, and the Wnt/β‐catenin pathway that interact at different stages during chondrogenesis.
Abstract: Chondrogenesis is the earliest phase of skeletal development, involving mesenchymal cell recruitment and migration, condensation of progenitors, and chondrocyte differentiation, and maturation and resulting in the formation of cartilage and bone during endochondral ossification. This process is controlled exquisitely by cellular interactions with the surrounding matrix, growth and differentiation factors, and other environmental factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporal-spatial manner. Vertebrate limb development is controlled by interacting patterning systems involving prominently the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and hedgehog pathways. Both positive and negative signaling kinases and transcription factors, such as Sox9 and Runx2, and interactions among them determine whether the differentiated chondrocytes remain within cartilage elements in articular joints or undergo hypertrophic maturation prior to ossification. The latter process requires extracellular matrix remodeling and vascularization controlled by mechanisms that are not understood completely. Recent work has revealed novel roles for mediators such as GADD45beta, transcription factors of the Dlx, bHLH, leucine zipper, and AP-1 families, and the Wnt/beta-catenin pathway that interact at different stages during chondrogenesis.
1,017 citations
Cites background from "Canonical WNT Signaling Promotes Os..."
...Recent reports from several groups indicate that Wnt signaling, via the canonical b-catenin pathway and activation of TCF/Lef transcription factors, functions in a cell autonomous manner to induce osteoblast differentiation and suppress chondrocyte differentiation in early chondroprogenitors [Day et al., 2005; Gaur et al., 2005; Glass et al., 2005; Hill et al., 2005; Hu et al., 2005]....
[...]
...…pathway and activation of TCF/Lef transcription factors, functions in a cell autonomous manner to induce osteoblast differentiation and suppress chondrocyte differentiation in early chondroprogenitors [Day et al., 2005; Gaur et al., 2005; Glass et al., 2005; Hill et al., 2005; Hu et al., 2005]....
[...]
TL;DR: Data demonstrate that commitment within the osteoblast lineage requires sequential, stage-specific, Ihh and canonical Wnt/β-catenin signaling to promote osteogenic, and block chondrogenic, programs of cell fate specification.
Abstract: Hedgehog and canonical Wnt/beta-catenin signaling are implicated in development of the osteoblast, the bone matrix-secreting cell of the vertebrate skeleton. We have used genetic approaches to dissect the roles of these pathways in specification of the osteoblast lineage. Previous studies indicate that Ihh signaling in the long bones is essential for initial specification of an osteoblast progenitor to a Runx2+ osteoblast precursor. We show here that this is a transient requirement, as removal of Hh responsiveness in later Runx2+, Osx1+ osteoblast precursors does not disrupt the formation of mature osteoblasts. By contrast, the removal of canonical Wnt signaling by conditional removal of the beta-catenin gene in early osteoblast progenitors or in Runx2+, Osx1+ osteoblast precursors results in a similar phenotype: osteoblasts fail to progress to a terminal osteocalcin+ fate and instead convert to a chondrocyte fate. By contrast, stabilization of beta-catenin signaling in Runx2+, Osx1+ osteoblast precursors leads to the premature differentiation of bone matrix secreting osteoblasts. These data demonstrate that commitment within the osteoblast lineage requires sequential, stage-specific, Ihh and canonical Wnt/beta-catenin signaling to promote osteogenic, and block chondrogenic, programs of cell fate specification.
927 citations
Cites background from "Canonical WNT Signaling Promotes Os..."
...Canonical Wnt ligands have been shown to stimulate Runx2 expression and Runx2 is itself essential for osteoblast development (Gaur et al., 2005)....
[...]
TL;DR: Runx2 inhibits osteoblast maturation and the transition into osteocytes, keeping osteoblasts in an immature stage, and β‐catenin, osterix, and Runx2 direct them to immature osteoblast, which produce bone matrix proteins, blocking their potential to differentiate into the chondrocytic lineage.
Abstract: Runx2, osterix, and beta-catenin are essential for osteoblast differentiation. Runx2 directs multipotent mesenchymal cells to an osteoblastic lineage, and inhibits them from differentiating into the adipocytic and chondrocytic lineages. After differentiating to preosteoblasts, beta-catenin, osterix, and Runx2 direct them to immature osteoblasts, which produce bone matrix proteins, blocking their potential to differentiate into the chondrocytic lineage. Runx2 inhibits osteoblast maturation and the transition into osteocytes, keeping osteoblasts in an immature stage. Other transcription factors including Msx1, Msx2, Dlx5, Dlx6, Twist, AP1(Fos/Jun), Knox-20, Sp3, and ATF4 are also involved in osteoblast differentiation. To gain an understanding of bone development, it is important to position these transcription factors to the right places in the processes of osteoblast differentiation.
906 citations
Cites background from "Canonical WNT Signaling Promotes Os..."
...Further, b-catenin/TCF1 enhances Runx2 expression and Runx2 promoter activity [Gaur et al., 2005]....
[...]
TL;DR: Recent advances in understanding the cellular and molecular signaling pathways and global transcriptional regulators of adult mesenchymal stem cells have provided new insights into their biology and potential clinical applications, particularly for tissue repair and regeneration.
Abstract: Recent advances in understanding the cellular and molecular signaling pathways and global transcriptional regulators of adult mesenchymal stem cells have provided new insights into their biology and potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal and regulation of lineage-specific differentiation of mesenchymal stem cells. In addition we review recent research on the concept of stem cell niche, and its relevance to adult mesenchymal stem cells.
888 citations
Cites background from "Canonical WNT Signaling Promotes Os..."
...Chromatin immunoprecipitation and promoter mutational analyses showed that β-catenin/LEF (lymphoid enhancer binding factor)/TCF1 (T-cell factor 1) occupy a cognate binding site in the proximal runx2 promoter and may therefore directly regulate runx2 expression [50]....
[...]
References
More filters
TL;DR: The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels, and that receptor-ligand specificity and feedback loops help to determine WNT signaling outputs.
Abstract: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
5,129 citations
TL;DR: Cloned cDNA encoding Osf2/Cbfa1 is identified as an osteoblast-specific transcription factor and as a regulator of osteoblasts differentiation.
4,198 citations
TL;DR: The data suggest that both intramembranous and endochondral ossification were completely blocked, owing to the maturational arrest of osteoblasts in the mutant mice, and demonstrate that Cbfa1 plays an essential role in osteogenesis.
4,196 citations
TL;DR: The Cbfa1 gene is essential for osteoblast differentiation and bone formation, and the C bfa1 heterozygous mouse is a paradigm for a human skeletal disorder.
2,822 citations
TL;DR: It is reported that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth and is important for the establishment of peak bone mass.
2,210 citations