Abstract
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.
Highlights
Osteoporosis is a metabolic disease characterized by progressive bone loss leading to skeletal fragility and fracture [1]
Osteoporosis is a common disease strongly influenced by genetics
We conducted a genome wide association study (GWAS) using the ability of the osteoblast to make bone-like mineralized nodules in vitro as a simpler phenotype to find genes that have a robust impact on bone
Summary
Osteoporosis is a metabolic disease characterized by progressive bone loss leading to skeletal fragility and fracture [1]. 200 million people worldwide have or are at risk of developing osteoporosis [2], leading to ~8.6 million fractures annually [3]. As the proportion of aged persons worldwide is increasing, osteoporosis is becoming an even greater public health burden [4]. History remains the strongest risk factor for development of osteoporosis and studies in animal models reinforce that this is a complex genetic disease [8,9,10]. Increasing our understanding of the genes influencing osteoporosis is critical for the development of approaches for its treatment and prevention
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