title: 24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturation.
abstract: Vitamin D receptor (VDR) agonists supporting human osteoblast (hOB) differentiation in the absence of bone resorption are attractive agents in a bone regenerative setting. One potential candidate fulfilling these roles is 24,25-dihydroxy vitamin D3 (24,25D). Over forty years ago it was reported that supraphysiological levels of 24,25D could stimulate intestinal calcium uptake and aid bone repair without causing bone calcium mobilisation. VDR agonists co-operate with certain growth factors to enhance hOB differentiation but whether 24,25D might act similarly in promoting cellular maturation has not been described. Given our discovery that lysophosphatidic acid (LPA) co-operated with VDR agonists to enhance hOB maturation, we co-treated MG63 hOBs with 24,25D and a phosphatase-resistant LPA analog. In isolation 24,25D inhibited proliferation and stimulated osteocalcin expression. When co-administered with the LPA analog there were synergistic increases in alkaline phosphatase (ALP). These are encouraging findings which may help realise the future application of 24,25D in promoting osseous repair.
authors: Musculoskeletal Research Unit, Avon Orthopaedic Centre, Southmead Hospital, Bristol BS10 5NB, UK.
authors: Sarah Tamar
authors: ST
authors: Lancaster
authors: Musculoskeletal Research Unit, Avon Orthopaedic Centre, Southmead Hospital, Bristol BS10 5NB, UK.
authors: Julia
authors: J
authors: Blackburn
authors: Musculoskeletal Research Unit, Avon Orthopaedic Centre, Southmead Hospital, Bristol BS10 5NB, UK.
authors: Ashley
authors: A
authors: Blom
authors: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
authors: Makoto
authors: M
authors: Makishima
authors: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
authors: Michiyasu
authors: M
authors: Ishizawa
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK. Electronic address: jason.mansell@uwe.ac.uk.
authors: Jason Peter
authors: JP
authors: Mansell
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000737:chemistry / Q000494:pharmacology*; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000378:metabolism*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D015675:Osteocalcin / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D005456:Fluorescent Dyes; D008934:Mitogens; D063065:Organophosphonates; D018167:Receptors, Calcitriol; D049368:Receptors, Lysophosphatidic Acid; C410228:ZK159222; D015675:Osteocalcin; D015650:24,25-Dihydroxyvitamin D 3; D014212:Tretinoin; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D007654:Ketoconazole
keywords: 24,25-Dihydroxy vitamin D3; Alkaline phosphatase; Differentiation; Human osteoblasts; Lysophosphatidic acid; Osteocalcin