Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America.
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
PLoS Genet. 2020 Jun 4;16(6):e1008805. doi: 10.1371/journal.pgen.1008805. eCollection 2020 Jun.
Osteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.
骨质疏松症是一种遗传性疾病，其特征是骨矿物质密度（BMD）逐渐降低，导致骨折风险增加。在过去的十年中，全基因组关联研究（GWAS）已经确定了超过 1000 个与 BMD 相关的基因。然而，作为一种表型，BMD 具有挑战性，因为骨骼是一种受局部和全身生理影响的多细胞组织。在这里，我们专注于 BMD 的一个单一组成部分，即小鼠中的成骨细胞介导的骨形成，并确定了影响成骨细胞活性的关联，这些关联位于小鼠染色体（Chrs）1、4 和 17 上。Chr. 4 上的位点位于 Wnt4 和 Zbtb40 之间的基因间区域，与人的 BMD 基因座同源。我们测试了 Wnt4 和 Zbtb40 在成骨细胞活性和 BMD 中的作用。成骨细胞中 Zbtb40 的敲低而非 Wnt4 的敲低大大降低了矿化。此外，这两个基因的功能丧失型小鼠模型均表现出 BMD 降低。我们的研究结果强调，研究体外成骨细胞矿化的遗传基础可用于鉴定影响骨形成和 BMD 的基因。
