Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density

Abstract

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. IntroductionOsteoporosis is a disease characterized by low bone mass, skeletal fragility, and increased risk of fracture (1). Of the traits intrinsic to bone that influence its strength, bone mineral density (BMD) is one of the strongest predictors of fractures (2). BMD is also highly heritable, with approximately 70% of its variation being attributable to genetic factors. As a result, developing a comprehensive understanding of the genes and pathways that regulate BMD promises to lead to novel therapies aimed at preventing and treating bone fragility.Genome-wide association studies (GWAS) have significantly expanded the list of known variants and genes that influence BMD (3). A recent meta-analysis of 17 BMD GWAS (Genetic Effects For Osteoporosis [GEFOS] Consortium) involving approximately 83,000 individuals identified 56 robustly significant associations (4). Interestingly, together, the associations explained less than 5% of the total phenotypic variance in BMD, suggesting that bone mass is highly polygenic and that most of the genes influencing BMD remain to be identified.One strategy that can help fill this knowledge gap is the use of gene discovery in the mouse to inform human BMD GWAS. Several recent studies (5-10) have demonstrated the effectiveness of this strategy. To date, dozens of quantitative trait loci (QTLs) (regions of the genome harboring genetic variation influencing a quantitative trait) affecting BMD have been identified in the mouse (11), and recently the pace of identifying QTL genes has rapidly progressed. This is due in part to the development of sys-

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…For example, expression profiling in the HMDP was combined with siRNA validation to demonstrate that Cmc2 (2310061C15Rik) regulates the inflammatory response of macrophages . Gene expression data generated from the HMDP was similarly combined with expression data from other RI lines and studies of KO mice to identify a role for Bicc1 in determining bone mineral density (Mesner et al 2014). The CC was used to show that resistance to influenza A virus infection was largely due to variants in Mx1 (Ferris et al 2013).…”

Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis

“…Polycystins are also expressed in other tissues (22,23), and several extrarenal functions are being recognized (23,24), including in the skeleton (25,26), where recent evidence shows that the polycystin complex plays an important role in osteoblastogenesis to control bone formation (27)(28)(29). In this regard, osteoblastspecific deletion of Pkd1 or Pkd2 resulted in osteopenia, reduced runt-related transcription factor 2-dependent (Runx2-dependent) osteoblastogenesis, and impaired bone mechanosensing responses to in vivo mechanical loading in mice (30)(31)(32).…”

A gradient of maternal Bicaudal-C controls vertebrate embryogenesis via translational repression of mRNAs encoding cell fate regulators

“…For example, homozygous Bicc1 mutant mice develop into adults but exhibit defects of their kidneys, pancreas and heart (Maisonneuve et al, 2009). Some mutations in the human BICC1 gene are associated with the kidney disease cystic renal dysplasia, whereas others are associated with defects in bone density (Kraus et al, 2012;Mesner et al, 2014). Collectively, these examples reveal the importance of zygotically expressed Bicc1 to normal vertebrate development and health, but they do not address the role of maternal Bicc1 in vertebrate embryogenesis.…”