Genetic Screening of WNT4 and WNT5B in Two Populations with Deviating Bone Mineral Densities

Abstract

A role for WNT4 and WNT5B in bone metabolism was indicated by genome-wide association studies (GWAS) and a Wnt4 knockout mouse model. The aim of this study was therefore to replicate and further investigate the causality between genetic variation in WNT4 and WNT5B and deviating bone mineral density (BMD) values. A WNT4 and WNT5B mutation screening was performed in patients with craniotubular hyperostosis using Sanger sequencing. Here, no putative causal mutations were detected. Moreover, a high and low BMD cohort was selected from the Odense Androgen Study population for re-sequencing. In WNT4 we detected four variants (three rare, one common), while in WNT5B we detected five variants (two rare, three common). For the common variants, no significant difference in genotype frequencies between the high and low BMD cohorts was observed. The SNPs associated with the GWAS were genotyped in these cohorts, but again no significant difference in genotype frequencies was observed. Despite the findings of the GWAS, we were not able to replicate or further verify the genetic association of polymorphisms in WNT4 and WNT5B with BMD. In order to do so, the intronic regions of both genes could be investigated more thoroughly in more extended populations (or extremes) with greater power. Future genetic and functional studies toward adjacent genes of WNT4 and WNT5B can also be interesting to figure out whether the signal from GWAS could possibly be attributed to genetic variation in these genes.

Key Promoter Region of Wnt4 response to FSH and Genetic Effect on Several Production Traits of Its Mutations in Chicken

“…A genome-wide association study revealed that polymorphisms of Wnt4 were associated with bone mineral densities (Hendrickx et al, 2017), which is consistent with the result of our study. Keel bone health in laying hens is an important welfare problem in egg production systems.…”

“…The Wnt pathway is involved in bone and cartilage homeostasis, controls the function of osteoblasts, and affects the differentiation of osteoblasts (Huang et al, 2019; Guo and Cooper, 2007; Li et al, 2019). A genome-wide association study revealed that polymorphisms of Wnt4 were associated with bone mineral densities (Hendrickx et al, 2017), which is consistent with the result of our study. Keel bone health in laying hens is an important welfare problem in egg production systems.…”

Knockout of TLR4 promotes fracture healing by activating Wnt/β-catenin signaling pathway

“…A previous study shows that Wnt4 can prevent osteoclast formation and bone resorption 34 . Hendrickx et al found that Wnt4 and Wnt5B participated in bone metabolism 35 . Heras et al revealed that the expression levels of βcatenin, Wnt4 and Wnt5B were proportional to the osteogenic ability of osteoblasts 36 .…”

Efeitos das interações entre células-tronco mesenquimais de ratos saudáveis e com osteoporose, diabetes mellitus ou hipertensão arterial na diferenciação osteoblástica e na regeneração de defeitos ósseos

“…Devemos considerar ainda a complexidade da diferenciação osteoblástica, onde muitos genes das vias avaliadas participam de funções biológicas diversas, tais como proliferação, diferenciação e migração celular, desenvolvimento embrionário e esquelético, formação óssea, remodelação e reparo tecidual, defesa do hospedeiro e hemostasia. (YAN et al, 2022;YU et al, 2021;COSTANTINI et al, 2018;PERSSON et al, 2019;HENDRICKX et al, 2017;DOCHEVA et al, 2014;LIU et al, 2013;MULLIN et al, 2013;KATOH;KATOH, 2007) (HUAMAN et al 2019;WANG et al, 2019). Além disso, assim como apresentado aqui, estudos anteriores utilizando o mesmo modelo experimental mostraram que a utilização de células alógenas foi segura e induziu a formação de tecido ósseo após injeção nos defeitos (ADOLPHO et al, 2022;FREITAS et al, 2019a;FREITAS et al, 2019b;FREITAS et al, 2017).…”

“…A partir das análise de PCR array tanto em meio normoglicêmico quanto hiperglicêmico, não se descarta que outras vias de sinalização, não avaliadas nesse estudo, possam estar envolvidas na diferenciação osteoblástica, além de se considerar ainda a complexidade desse processo, onde muitos genes das vias avaliadas participam de funções biológicas diversas, tais como proliferação, diferenciação e migração celular, desenvolvimento embrionário e esquelético, formação óssea, remodelação e reparo tecidual, defesa do hospedeiro e hemostasia. (YAN et al, 2022;YU et al, 2021;COSTANTINI et al, 2018;PERSSON et al, 2019;HENDRICKX et al, 2017;DOCHEVA et al, 2014;LIU et al, 2013;MULLIN et al, 2013;KATOH;KATOH, 2007).…”