title: Chitinase 3-like 1 expression by human (MG63) osteoblasts in response to lysophosphatidic acid and 1,25-dihydroxyvitamin D3.
abstract: Chitinase 3-like 1, otherwise known as YKL-40, is a secreted glycoprotein purported to have a role in extracellular matrix metabolism. The first mammalian cell type found to express YKL-40 was the human osteosarcoma-derived osteoblast, MG63. In that first study the active vitamin D3 metabolite, 1,25-dihydroxycholecalciferol (1,25D), stimulated YKL-40 expression, thereby indicating that a vital factor for skeletal health promoted YKL-40 synthesis by bone forming cells. However, when these MG63 cells were exposed to 1,25D they were also exposed to serum, a rich source of the pleiotropic lipid mediator, lysophosphatidic acid (LPA). Given that 1,25D is now known to co-operate with selected growth factors, including LPA, to influence human osteoblast differentiation we hypothesised that 1,25D and LPA may work together to stimulate osteoblast YKL-40 expression. Herein we report that 1,25D and LPA synergistically promote YKL-40 expression by MG63 cells. Inhibitors targeting AP1, MEK, Sp1 and STAT3 blunted the expression of both alkaline phosphatase and YKL-40 by MG63 cells in response to co-stimulation with 1,25D and LPA. Other ligands of the vitamin D receptor also co-operated with LPA in driving YKL-40 mobilisation. Collectively our findings highlight another important role of 1,25D and LPA in the regulation of human osteoblast function.
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: J P
authors: JP
authors: Mansell
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK.
authors: M
authors: M
authors: Cooke
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK.
authors: M
authors: M
authors: Read
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK.
authors: H
authors: H
authors: Rudd
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK.
authors: A I
authors: AI
authors: Shiel
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK.
authors: K
authors: K
authors: Wilkins
authors: Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK.
authors: M
authors: M
authors: Manso
mesh_terms: D045744:Cell Line, Tumor; D000071451:Chitinase-3-Like Protein 1 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011422:Propionates / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D014815:Vitamins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D013755:Tetradecanoylphorbol Acetate; C032881:lysophosphatidic acid
keywords: Active vitamin D; Alkaline phosphatase; Differentiation; Lysophosphatidic acid; Osteoblasts; YKL-40