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 1000 多个 BMD 关联。然而，骨密度的表型具有挑战性，因为骨是一种受局部和全身生理学影响的多细胞组织。在这里，我们关注 BMD 的单一组成部分，即小鼠中成骨细胞介导的骨形成，并确定了影响小鼠染色体 (Chrs) 1、4 和 17 上成骨细胞活性的关联。 4 位于Wnt4和Zbtb40之间的基因间区域，与人类 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 ）显着降低了矿化。此外，这两个基因功能丧失的小鼠模型表现出骨密度降低。我们的结果强调，研究体外成骨细胞矿化的遗传基础可用于识别影响骨形成和 BMD 的基因。