Wnt16 is Involved in Intramembranous Ossification and Suppresses Osteoblast Differentiation Through the Wnt/β‐Catenin Pathway

Jiang, Zheng; Hoff, Johannes W. Von den; Torensma, Ruurd; Meng, Liuyan; Bian, Zhuan

doi:10.1002/jcp.24460

Cited by 40 publications

(40 citation statements)

References 49 publications

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“…(51–53) Wnt16 is expressed in osteoid tissue of craniofacial bones during embryonic development in mice, and suppresses osteoblast differentiation through the canonical β-catenin pathway in MC3T3-E1 preosteoblasts. (54) Several GWA meta-analysis studies have demonstrated that WNT16 intron 3 SNP rs3801387, (41) exon 2 rs2908004 (WNT16B G82R) and exon 4 rs2707466 (WNT16B T263I) (55,56) as well as intergenic SNP rs10242100 (31) are associated with BMD phenotypes (Figure 3). However, functional roles of non-coding SNPs rs10242100 and rs3801387, which are in almost perfect LD [ r 2 = 0.915 in 1KG Pilot 1 CEU Population by applying SNAP tool (46) ], remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies

Niu

Liu

Xun

et al. 2015

Journal of Bone and Mineral Research

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Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-, total hip (HIP)-, and Lumbar Spine (LS)-BMD phenotypes. In stage 1, 9,593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21×10−6 (0.05/9,593) and 1.00×10−4, respectively. In stage 2, 9 stage 1-discovered phosSNPs (based on α = 1.00×10−4) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56×10−3, 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in 3 stages combined, achieving GWS for both FN-BMD (P-value = 8.36×10−10, 5.26×10−10, and 3.01×10−10, respectively) and HIP-BMD (P-value = 3.26×10−6, 1.97×10−6, and 1.63×10−12, respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analysis predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants.

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Section: Discussionmentioning

confidence: 99%

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies

Niu

Liu

Xun

et al. 2015

Journal of Bone and Mineral Research

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“…With regard to bone, we and others have recently shown that in osteoblasts Wnt16 signals via the canonical WNTcascade. 40,41 However, in contrast with the emergent hypothesis that Wnt16 has a positive effect on bone (similar to activation of canonical WNT signaling) and with the findings that Wnt16 deletion leads to decreased WNT signaling in cortical bone, Hendrickx et al 34 have reported that one of the WNT16 single-nucleotide polymorphisms, which falls in the Kozak sequence of WNT16 and is associated with increased WNT16 translation and increased BMD, does not activate b-catenin-dependent signaling. This suggests that either Wnt16 is a weak canonical WNT ligand in osteoblasts and/or that its ability to activate the canonical cascade may be dependent on multiple stochastic changes in the levels of biological factors in the microenvironment and on the presence and/or variations in the levels of specific receptors, antagonists and agonists.…”

Section: Wnt16 and The Regulation Of Bone Homeostasismentioning

confidence: 98%

“…40 Recently, our studies have shed light on the role of Wnt16 in postnatal bone homeostasis in mice and in the mechanism(s) by which this WNT ligand affects bone biology. 40,41 The first study demonstrating that Wnt16 contributes to cortical bone mass in mice was part of the Lexicon's Genome5000 program focused to characterize mouse knockout phenotypes of genes with pharmaceutical potential. These initial findings were included in two BMD GWAS, in which A new WNT on the bone F Gori et al the WNT16 gene was found to be strongly associated with cortical bone thickness and fracture susceptibility in humans.…”

Section: Wnt16 and The Regulation Of Bone Homeostasismentioning

confidence: 99%

A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

Gori¹,

Lerner²,

Ohlsson³

et al. 2015

BoneKEy Reports

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The last decade has provided abundant data implicating the WNT pathway in bone development and in the regulation of skeletal homeostasis. Rare human mutations together with gain-and loss-of-function approaches in mice have clearly demonstrated that disrupted regulation of this pathway leads to altered bone mass. In addition to these rare human and mice mutations, large population-based genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in B60 loci strongly associated with variations in bone mineral density (BMD) at different skeletal sites. Among the loci/genes identified by BMD GWAS, components of the WNT signaling pathway are numerous and have been shown to contribute to skeletal development and homeostasis. Within the components of WNTsignaling, the gene coding for WNT16, one of the 19 WNT ligands of the human genome, has been found strongly associated with specific bone traits such as cortical bone thickness, cortical porosity and fracture risk. Recently, the first functional characterization of Wnt16 has confirmed the critical role of Wnt16 in the regulation of cortical bone mass and bone strength in mice. These reports have extended our understanding of Wnt16 function in bone homeostasis and have not only confirmed the unique association of Wnt16 with cortical bone and fracture susceptibility, as suggested by GWAS in human populations, but have also provided novel insights into the biology of this WNT ligand and the mechanism(s) by which it regulates cortical but not trabecular bone homeostasis. Most interestingly, Wnt16 appears to be a strong anti-resorptive soluble factor acting on both osteoblasts and osteoclast precursors. WNT Signaling and Skeletal HomeostasisSkeletal homeostasis is maintained throughout life by the balance between bone formation by osteoblasts (which derive from mesenchymal cells) and bone resorption by osteoclasts (which have hematopoietic origin), regulated in part by the third bone cell type, the osteocyte, itself derived from osteoblasts. The adult skeleton continuously undergoes remodeling, and failure to balance these two processes can lead to skeletal diseases, such as osteoporosis, characterized by decreased bone mass, altered bone micro-structure and increased risk of fragility fractures.1 Most studies have, however, focused on trabecular bone remodeling despite the fact that 80% of the skeleton is constituted by cortical bone. [2][3][4] The findings that with aging 80% of fractures are associated with cortical bone (non-vertebral fractures) indicate that cortical bone mass is a key determinant of bone strength. [2][3][4] Although the risk of vertebral fractures, which arise mainly at trabecular sites, is significantly decreased by the currently available anti-resorptive or anabolic treatments, the risk of non-vertebral fractures is reduced only by B20%, confirming a dichotomy between the homeostatic regulation of the trabecular and cortical bone compartments 1,[5][6][7][8]

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“…The Notch signaling pathway has also been linked to craniosynostosis as a result of its association with tissue boundary formation, which is important during the patterned growth of the skull (Yen et al, 2010). Additionally, a microarray study has identified upregulation of Wnt signaling in tissues (Miraoui et al, 2010), and other studies have identified WNT5B expression in postnatal growth plates (Andrade et al, 2007) and WNT16 as suppressing osteoblast differentiation in craniofacial bone formation (Jiang et al, 2014). Here, we used correlation analysis to investigate whether these transcripts are associated with SSC.…”

Section: −4mentioning

confidence: 99%

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

Al-Rekabi

Wheeler

Leonard

et al. 2016

Journal of Cell Science

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Insulin growth factor 1 (IGF1) is a major anabolic signal that is essential during skeletal development, cellular adhesion and migration. Recent transcriptomic studies have shown that there is an upregulation in IGF1 expression in calvarial osteoblasts derived from patients with singlesuture craniosynostosis (SSC). Upregulation of the IGF1 signaling pathway is known to induce increased expression of a set of osteogenic markers that previously have been shown to be correlated with contractility and migration. Although the IGF1 signaling pathway has been implicated in SSC, a correlation between IGF1, contractility and migration has not yet been investigated. Here, we examined the effect of IGF1 activation in inducing cellular contractility and migration in SSC osteoblasts using micropost arrays and time-lapse microscopy. We observed that the contractile forces and migration speeds of SSC osteoblasts correlated with IGF1 expression. Moreover, both contractility and migration of SSC osteoblasts were directly affected by the interaction of IGF1 with IGF1 receptor (IGF1R). Our results suggest that IGF1 activity can provide valuable insight for phenotype-genotype correlation in SSC osteoblasts and might provide a target for therapeutic intervention.

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Wnt16 is Involved in Intramembranous Ossification and Suppresses Osteoblast Differentiation Through the Wnt/β‐Catenin Pathway

Cited by 40 publications

References 49 publications

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies

A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

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