title: Early response of the human SOST gene to stimulation by 1α,25-dihydroxyvitamin D3.
abstract: The osteocyte expressed gene SOST encodes sclerostin, a potent negative regulator of bone formation and inducer of bone resorption. We have recently demonstrated that the human SOST gene is positively regulated in response to 1α,25-dihydroxyvitamin D3(1,25D). Responsiveness may be mediated at least in part by a single classical DR3-type vitamin D response element (VDRE). In this study we examined the early responsiveness of the SOST gene to both 1,25D and to parathyroid hormone (PTH), a known repressor of SOST expression, in SaOS2 cells differentiated to an osteocyte-like stage of cell maturation. Both SOST mRNA levels and sclerostin protein levels increased in these cultures as early as 3h post-treatment with 1,25D and declined in response to PTH in the same timeframe. For 1,25D, the level of induced SOST appeared dependent on the extent, to which the degradative enzyme 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1) was induced. Together with the observed rapid decrease in SOST/sclerostin levels in response to PTH, endocrine regulation of sclerostin production appears to be an important determinant of sclerostin levels. These findings confirm that the human SOST gene and sclerostin expression can be considered to be directly 1,25D-responsive in osteocytes.
authors.affiliation: Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia. Electronic address: asiri.wijenayaka@adelaide.edu.au.
authors.forename: Asiri R
authors.initials: AR
authors.lastname: Wijenayaka
authors.affiliation: Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Prideaux
authors.affiliation: Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Yang
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Morris
authors.affiliation: Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Anderson
authors.affiliation: Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D010281:Parathyroid Hormone; D053245:RANK Ligand; C422903:SOST protein, human; C505688:TNFSF11 protein, human; D015675:Osteocalcin; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
keywords: 1,25-Dihydoxyvitamin D; Osteocyte; Sclerostin