Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density.
Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network-based approach to determine how Bicc1 influences BMD. Based on this analysis, we inferred that Bicc1 was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency-dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Bicc1 as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels.
Larry D
LD
Mesner
Brianne
B
Ray
Yi-Hsiang
YH
Hsu
Ani
A
Manichaikul
Eric
E
Lum
Elizabeth C
EC
Bryda
Stephen S
SS
Rich
Clifford J
CJ
Rosen
Michael H
MH
Criqui
Matthew
M
Allison
Matthew J
MJ
Budoff
Thomas L
TL
Clemens
Charles R
CR
Farber
D000818:Animals; D015519:Bone Density / Q000235:genetics*; D002243:Carbolines; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins / Q000235:genetics*; D050396:TRPP Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics
D002243:Carbolines; D002352:Carrier Proteins; D016601:RNA-Binding Proteins; D050396:TRPP Cation Channels; C571508:Bicc1 protein, human; C540667:Bicc1 protein, mouse; C470988:GWC20