Genetic analysis of osteoblast activity identifies Zbtb40 as a regulator of osteoblast activity and bone mass


Autoři: Madison L. Doolittle aff001;  Gina M. Calabrese aff002;  Larry D. Mesner aff002;  Dana A. Godfrey aff004;  Robert D. Maynard aff001;  Cheryl L. Ackert-Bicknell aff001;  Charles R. Farber aff002
Působiště autorů: Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America aff001;  Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America aff002;  Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, United States of America aff003;  Department of Orthopedics, University of Colorado, Aurora, Colorado, United States of America aff004;  Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America aff005
Vyšlo v časopise: Genetic analysis of osteoblast activity identifies Zbtb40 as a regulator of osteoblast activity and bone mass. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008805
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008805

Souhrn

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.

Klíčová slova:

Alizarin staining – Bone fracture – Genetic loci – Genome-wide association studies – Mouse models – Osteoblast differentiation – Osteoblasts – Osteoporosis


Zdroje

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