title: Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment.
abstract: BACKGROUND
  Growth hormone (GH) substitution of adult-onset growth hormone deficiency (aoGHD) patients partially reverses unfavorable body composition profile. Wnt signaling pathway has being acknowledged as an important modulator of bone mass and of energy metabolism in adipose tissue and in β-cells.
  
  
  OBJECTIVE
  To assess the role of selected Wnt antagonists in bone and glucose metabolism before and after GH replacement in aoGHD.
  
  
  METHODS
  Patients from two randomized placebo-controlled studies of GH replacement in aoGHD were used. In study 1, 39 patients received GH or placebo for 9 months with 4 months wash-out. In study 2, iliac bone biopsies were obtained before and after GH or placebo (n = 10 each) for 12 months. Body composition and serum (study 1) and bone matrix (study 2) levels of Wnt antagonists (DKK-1, sFRP-3, WIF-1, and SOST) were quantified before and after GH. In vitro effect of GH and IGF-1 on DKK-1 secretion and expression of Wnt signaling modulators was assessed in human osteoblasts and mature adipocytes.
  
  
  RESULTS
  GH replacement increased circulating and bone matrix levels of DKK-1, but not sFRP-3, WIF-1, and SOST. Furthermore, DKK-1 secretion increased in human osteoblasts stimulated by GH in vitro, with no effects on other cells. At baseline and after treatment, circulating DKK-1 was negatively associated with bone mass, but not fat mass or measures of insulin resistance, in aoGHD patients.
  
  
  CONCLUSIONS
  An increase in DKK-1 may limit the effects of GH on bone mass, but does not seem to impact the increase in insulin resistance following GH substitution.
authors.affiliation: Research Institute for Internal Medicine (T.U., K.O., P.A., T.L.), Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine (T.U., N.C.O., K.O., P.A., T.L., J.B.), University of Oslo, Norway; K.G. Jebsen Inflammatory Research Center (T.U., P.A.), University of Oslo, Oslo, Norway; Section of Specialized Endocrinology, Department of Endocrinology (N.C.O., A.P.J., K.G., J.B.), Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases (P.A.), Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Nicoleta Cristina
authors.initials: NC
authors.lastname: Olarescu
authors.forename: Anders P
authors.initials: AP
authors.lastname: Jørgensen
authors.forename: Kari
authors.initials: K
authors.lastname: Otterdal
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Kristin
authors.initials: K
authors.lastname: Godang
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000378:metabolism; D004393:Dwarfism, Pituitary / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005819:Genetic Markers; D019382:Human Growth Hormone / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007085:Ilium / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000097:blood / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000097:blood / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; C455624:MYOZ3 protein, human; D009124:Muscle Proteins; D012097:Repressor Proteins; C422903:SOST protein, human; C485569:WIF1 protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I