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- Title
Genetic analysis of osteoblast activity identifies Zbtb40 as a regulator of osteoblast activity and bone mass.
- Authors
Doolittle, Madison L.; Calabrese, Gina M.; Mesner, Larry D.; Godfrey, Dana A.; Maynard, Robert D.; Ackert-Bicknell, Cheryl L.; Farber, Charles R.
- 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. Author summary: Osteoporosis is a common disease strongly influenced by genetics. Bone mineral density (BMD) is used clinically to predict fracture risk and has been used as a phenotype to identify genetic loci and genes impacting bone physiology. However, BMD is a complicated phenotype, impacted by a myriad of environmental factors and by two tissue-level processes: bone resorption and formation. 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. We identified Zbtb40 as a previously unappreciated regulator of osteoblast function and as a likely candidate gene for a genomic locus we identified for mineralized nodule formation on mouse Chromosome 4. This locus was one of the first identified for BMD in mice and is homologous for a GWAS locus on human Chromosome 1 for BMD. Further, we determined that Wnt4 may be a candidate gene for the mouse BMD locus, but is less likely to be a candidate for the osteoblast function locus. These data suggest that Zbtb40 may represent a novel target for future osteoporosis therapeutics that are anabolic for bone.
- Subjects
BONES; BONE density; OSTEOBLASTS; HUMAN chromosomes; BONE growth; BONE resorption; GENETICS
- Publication
PLoS Genetics, 2020, Vol 16, Issue 6, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1008805