title: Impaired bone formation in Pdia3 deficient mice.
abstract: 1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] is crucial for normal skeletal development and bone homeostasis. Protein disulfide isomerase family A, member 3 (PDIA3) mediates 1α,25(OH)2D3 initiated-rapid membrane signaling in several cell types. To understand its role in regulating skeletal development, we generated Pdia3-deficient mice and examined the physiologic consequence of Pdia3-disruption in embryos and Pdia3+/- heterozygotes at different ages. No mice homozygous for the Pdia3-deletion were found at birth nor were there embryos after E12.5, indicating that targeted disruption of the Pdia3 gene resulted in early embryonic lethality. Pdia3-deficiency also resulted in skeletal manifestations as revealed by µCT analysis of the tibias. In comparison to wild type mice, Pdia3 heterozygous mice displayed expanded growth plates associated with decreased tether formation. Histomorphometry also showed that the hypertrophic zone in Pdia3+/- mice was more cellular than seen in wild type growth plates. Metaphyseal trabecular bone in Pdia3+/- mice exhibited an age-dependent phenotype with lower BV/TV and trabecular numbers, which was most pronounced at 15 weeks of age. Bone marrow cells from Pdia3+/- mice exhibited impaired osteoblastic differentiation, based on reduced expression of osteoblast markers and mineral deposition compared to cells from wild type animals. Collectively, our findings provide in vivo evidence that PDIA3 is essential for normal skeletal development. The fact that the Pdia3+/- heterozygous mice share a similar growth plate and bone phenotype to nVdr knockout mice, suggests that PDIA3-mediated rapid membrane signaling might be an alternative mechanism responsible for 1α,25(OH)2D3's actions in regulating skeletal development.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Nizkorodov
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Kelsie
authors.initials: K
authors.lastname: Riemenschneider
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Christopher S D
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Rene
authors.initials: R
authors.lastname: Olivares-Navarrete
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America; Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017353:Gene Deletion; D006132:Growth Plate / Q000196:embryology / Q000378:metabolism; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*
chemical_list: C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases