Functional validation of the osteoporosis GWAS candidate FUBP3 in knockout mice

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Osteoporosis affects millions of people worldwide, resulting in an enormous healthcare burden and major socioeconomic costs.Bone mineral density (BMD) is a highly heritable quantitative trait and the major risk factor for fracture.We and others have identified noncoding single nucleotide polymorphisms that define an independent locus on chromosome 9 associated with both height and BMD in large scale GWAS.FUBP3 is the closest coding gene and is expressed in osteoclasts and cells of the osteoblast lineage.FUBP3 is a DNA and RNA binding protein and transcriptional regulator of c-myc.Although myc has been implicated in the maintenance of bone mass during aging, the role of FUBP3 in bone is unknown.We hypothesised that FUBP3 represents the causative gene at this locus and investigated its functional role in the skeleton in vivo.FUBP3 deficient mice (Fubp3 -/-, n=6-9 per sex, per genotype, per age, local ethical approval) had short stature at postnatal day 70 (P70) (vs.WT, pb 0.001, ANOVA) and P183 (vs.WT, pb 0.001, ANOVA).Caudal vertebrae were correspondingly short at P21 (vs.WT, pb 0.05, ANOVA), P70 (vs.WT, pb 0.001, ANOVA) and P183 (vs.WT, pb 0.001, ANOVA).Bone mineral content, measured by x-ray microradiography, was decreased in femurs (vs.WT, pb 0.05, Kolmogorov-Smirnov test) and caudal vertebrae (vs.WT, pb 0.01, Kolmogorov-Smirnov test), but markedly decreased in lumbar vertebrae (vs.WT, pb 0.001, Kolmogorov-Smirnov test).Adult Fubp3 -/-mice also displayed reduced femoral trabecular thickness and BMD determined by micro-CT (vs.WT, pb 0.05, ANOVA).Together, these data provide functional evidence of a novel role for FUBP3 in bone development and maintenance, defining FUBP3 as the causative gene associated with BMD at this GWAS locus.

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