title: New insights on membrane mediated effects of 1α,25-dihydroxy vitamin D3 signaling in the musculoskeletal system.
abstract: 1α,25-Dihydroxy vitamin D3 [1α,25(OH)2D3] acts on cells via classical steroid hormone receptor-mediated gene transcription and by initiating rapid membrane-mediated signaling pathways. Two receptors have been implicated to play roles in 1α,25(OH)2D3 mediated rapid signaling, the classical nuclear vitamin D receptor (VDR) and protein disulfide isomerase, family A, member 3 (Pdia3). Long term efforts to investigate the roles of these two receptors demonstrated thatPdia3 is located in caveolae, where it interacts with phospholipase A2 (PLA2) activating protein (PLAA) and caveolin-1 (Cav-1) to initiate rapid signaling via Ca(++)/calmodulin-dependent protein kinase II (CaMKII), PLA2, phospholipase C (PLC), protein kinase C (PKC), and ultimately the ERK1/2 family of mitogen activated protein kinases (MAPK). VDR is present on the plasma membrane, and it is required for 1α,25(OH)2D3 induced rapid activation of Src. PDIA3+/- mice demonstrate an impaired musculoskeletal phenotype. Moreover, our studies examining mineralization of pre-osteoblasts in 3D culture have shown the physiological importance of Pdia3 and VDR interaction: knockdown of Pdia3 or VDR is characterized by impaired mineralization of the constructs.
authors.affiliation: School of Biology, Georgia Institute of Technology, 310 Ferst Dr. NW, Atlanta, GA, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Doroudi
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jiaxuan
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Biology, Georgia Institute of Technology, 310 Ferst Dr. NW, Atlanta, GA, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; School of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA, USA.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
authors.affiliation: School of Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA, USA; Department of Periodontics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Electronic address: zschwartz@vcu.edu.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009141:Musculoskeletal System / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051242:Caveolin 1; D018167:Receptors, Calcitriol; C579457:VDR protein, human; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010738:Type C Phospholipases; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human
keywords: 1α,25(OH)(2)D(3); BMP2; CaMKII; Mineralization; Osteoblast; Pdia3