Bone Abstracts (2014) 3 OC5.5 | DOI: 10.1530/boneabs.3.OC5.5

Rs55710688 in the Kozak sequence of WNT16 increases translation efficiency and is associated with osteoporosis related parameters

Gretl Hendrickx1, Eveline Boudin1, Igor Fijalkowski1, Torben Leo Nielsen2, Marianne Andersen2, Kim Brixen2 & Wim Van Hul1


1Department of Medical Genetics, University of Antwerp, Antwerp, Belgium; 2Department of Endocrinology, Odense University Hospital, Odense, Denmark.


Recent studies confirmed the role of WNT16 in bone mineral density (BMD), bone strength and fracture risk. These findings made WNT16 interesting for further genetic and functional studies to clarify its effect on osteoporosis related parameters.

A WNT16 candidate gene association study was performed in men from the Odense Androgen Study (OAS). Five tagSNPs and one multimarker test were selected for genotyping to cover most of the common genetic variation in and around WNT16. This study confirmed previously reported associations for rs3801387 and rs2707466 and additionally showed a strong association between rs2908007 and BMD at several sites. Next, re-sequencing of WNT16 was performed on two cohorts selected from the young OAS cohort, based on extreme BMD values. Rs55710688 showed a significant difference in genotype frequencies between the two BMD cohorts. This variant was selected for an in vitro translation experiment since it is located in the Kozak sequence of the WNT16a transcript. We observed an increased translation efficiency and thus a higher amount of WNT16a generated from the Kozak sequence that was significantly more prevalent in the high BMD cohort. This observation is in line with the results of the Wnt16−/− mice. Finally, a WNT luciferase reporter assay was performed in HEK293T cells and unexpectedly showed no activation of canonical WNT signaling by Wnt16. Moreover, a dose-dependent inhibitory effect of Wnt16 on WNT1 activation of this pathway was detected. This is in contrast with the known activating effect of canonical WNT signaling on bone formation. Therefore, the assay was performed in Saos-2 cells, a human osteosarcoma cell line. Preliminary results do show an significant activation of canonical signaling by Wnt16 in Saos-2 cells.

Our results strongly suggest that WNT16 is most likely able to increase BMD, by stimulation of canonical WNT signaling in bone forming cells. More research, including in vivo studies, is required to verify this hypothesis.

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