title: Evidence for auto/paracrine actions of vitamin D in bone: 1alpha-hydroxylase expression and activity in human bone cells.
abstract: Vitamin D is an important regulator of mineral homeostasis and bone metabolism. 1Alpha-hydroxylation of 25-(OH)D3 to form the bioactive vitamin D hormone, 1alpha,25-(OH)2D3, is classically considered to take place in the kidney. However, 1alpha-hydroxylase has been reported at extrarenal sites. Whether bone is a 1alpha,25-(OH)2D3 synthesizing tissue is not univocal. The aim of this study was to investigate an autocrine/paracrine function for 1alpha,25-(OH)2D3 in bone. We show that 1alpha-hydroxylase is expressed in human osteoblasts, as well as the vitamin D binding protein receptors megalin and cubilin. Functional analyses demonstrate that after incubation with the 1alpha-hydroxylase substrate 25-(OH)D3, the osteoblasts can produce sufficient 1alpha,25-(OH)2D3 to modulate osteoblast activity, resulting in induced alkaline phosphatase (ALP) activity, osteocalcin (OC) and CYP24 mRNA expression, and mineralization. The classical renal regulators of 1alpha-hydroxylase, parathyroid hormone, and ambient calcium do not regulate 1alpha-hydroxylase in osteoblasts. In contrast, interleukin (IL)-1beta strongly induces 1alpha-hydroxylase. Besides the bone-forming cells, we demonstrate 1alpha-hydroxylase activity in the bone resorbing cells, the osteoclasts. This is strongly dependent on osteoclast inducer RANKL. This study showing expression, activity, and functionality of 1alpha-hydroxylase unequivocally demonstrates that vitamin D can act in an auto/paracrine manner in bone.
authors.affiliation: Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Driel
authors.forename: M
authors.initials: M
authors.lastname: Koedam
authors.forename: C J
authors.initials: CJ
authors.lastname: Buurman
authors.forename: M
authors.initials: M
authors.lastname: Hewison
authors.forename: H
authors.initials: H
authors.lastname: Chiba
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: H A P
authors.initials: HA
authors.lastname: Pols
authors.forename: J P T M
authors.initials: JP
authors.lastname: van Leeuwen
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism*; D001842:Bone and Bones / Q000201:enzymology*; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D005270:Femur Head / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D010006:Osteoblasts / Q000201:enzymology*; D010010:Osteoclasts / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014807:Vitamin D / Q000494:pharmacology*
chemical_list: D014807:Vitamin D; D012313:RNA; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium