J Clin Invest. 2014 Jun;124(6):2736-49. doi: 10.1172/JCI73072. Epub 2014 May 1.
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.
患者的骨矿物质密度 (BMD) 预测骨质疏松性骨折的可能性。虽然在阐明 BMD 的遗传决定因素方面已经取得了很大进展，但我们对涉及的因素的理解仍然不完整。在这里，我们在小鼠中使用系统遗传学方法预测，编码 RNA 结合蛋白的双尾 C 同源物 1 (Bicc1) 是位于小鼠 10 号染色体上的 BMD 数量性状位点 (QTL) 的原因。与这一预测一致，Bicc1 杂合子缺失的小鼠 BMD 较低。我们使用基于共表达网络的方法来确定 Bicc1 如何影响 BMD。基于此分析，我们推断 Bicc1 参与成骨细胞分化，多囊肾病 2 (Pkd2) 是 Bicc1 的下游靶标。Bicc1 和 Pkd2 的敲低会损害成骨细胞的形成，而 Pkd2 的过表达可以挽救 Bicc1 缺陷依赖性的成骨细胞缺陷。最后，在 2 项人类 BMD 全基因组关联 (GWAS) 荟萃分析中，我们鉴定了与 BMD 相关的 BICC1 和 PKD2 中的 SNPs。这些在小鼠和人类中的结果都表明 Bicc1 是成骨细胞发生和 BMD 的遗传决定因素，并表明它通过调节 Pkd2 转录本水平来实现这一点。
