Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

Autor: Dana A. Godfrey, Charles R. Farber, Gina M. Calabrese, Cheryl L. Ackert-Bicknell, Larry D. Mesner, Robert D. Maynard, Madison L. Doolittle
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Cancer Research
Critical Care and Emergency Medicine
Osteoporosis
Genome-wide association study
Alizarin Staining
QH426-470
Mice
0302 clinical medicine
Animal Cells
Bone Density
Osteogenesis
Wnt4 Protein
Medicine and Health Sciences
Group-Specific Staining
Connective Tissue Diseases
Genetics (clinical)
Trauma Medicine
Cells
Cultured
Connective Tissue Cells
Staining
Bone mineral
0303 health sciences
Gene knockdown
Cell Differentiation
Osteoblast
Animal Models
Genomics
Phenotype
Osteoblast Differentiation
DNA-Binding Proteins
medicine.anatomical_structure
Experimental Organism Systems
Connective Tissue
Bone Fracture
Female
Cellular Types
Anatomy
Traumatic Injury
Research Article
musculoskeletal diseases
medicine.medical_specialty
Single-nucleotide polymorphism
Mouse Models
Locus (genetics)
Biology
Research and Analysis Methods
03 medical and health sciences
Model Organisms
Rheumatology
Internal medicine
Genome-Wide Association Studies
Genetics
medicine
Animals
Molecular Biology
Gene
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Genetic association
Osteoblasts
Biology and Life Sciences
Computational Biology
Human Genetics
Bone fracture
Cell Biology
Genome Analysis
medicine.disease
Mice
Inbred C57BL
Biological Tissue
Endocrinology
Genetic Loci
Specimen Preparation and Treatment
Animal Studies
030217 neurology & neurosurgery
Developmental Biology
Zdroj: PLoS Genetics, Vol 16, Iss 6, p e1008805 (2020)
PLoS Genetics
DOI: 10.1101/828525
Popis: 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.
Databáze: OpenAIRE
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