title: Elevated FGF21 leads to attenuated postnatal linear growth in preterm infants through GH resistance in chondrocytes.
abstract: BACKGROUND
  The hormone fibroblast growth factor 21 (FGF21) is a key metabolic regulator in the adaptation to fasting. In food-restricted mice, inhibition of skeletal growth is mediated by the antagonistic effect of FGF21 on GH action in the liver and growth plate.
  
  
  OBJECTIVE
  The objective of the study was to assess the role of FGF21 in growth regulation in humans using postnatal growth failure of very preterm infants as a model.
  
  
  METHODS
  FGF21 levels were measured serially in very preterm infants, and their linear growth evaluated from birth to term-equivalent age. Primary chondrocytes obtained from pediatric donors were used to test whether FGF21 can directly interfere with GH signaling.
  
  
  RESULTS
  A negative association (β -.415, P < .005, linear regression model) of FGF21 levels with the change in SD score for length was found. In primary chondrocytes, FGF21 upregulated basal and GH-induced SOCS2 expression and inhibited GH-induced signal transducer and activator of transcription 5 (STAT5) phosphorylation as well as GH-induced COLII and ALP expression. Finally, FGF21 inhibited GH-induced IGF-1 expression and cell proliferation, indicating GH resistance. However, FGF21 did not affect IGF-1-induced cell proliferation.
  
  
  CONCLUSIONS
  Elevated FGF21 serum levels during the first weeks of life are independently associated with postnatal growth failure in preterm infants. Furthermore, our data provide mechanistic insights into GH resistance secondary to prematurity and may offer an explanation for the growth failure commonly seen in chronic conditions of childhood.
authors.affiliation: Centre for Endocrinology (L.G., L.D.), William Harvey Research Institute, Barts and the London, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pediatrics (S.S., U.S.), Kuopio University Hospital, 70210 Kuopio, Finland; Department of Plastic Surgery (N.W.B.), Great Ormond Street Hospital for Children National Health Service Trust, London WC1N 3JH, United Kingdom; and Developmental Biology Unit (P.F.), University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Guasti
authors.forename: Sanna
authors.initials: S
authors.lastname: Silvennoinen
authors.forename: Neil W
authors.initials: NW
authors.lastname: Bulstrode
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferretti
authors.forename: Ulla
authors.initials: U
authors.lastname: Sankilampi
authors.forename: Leo
authors.initials: L
authors.lastname: Dunkel
mesh_terms: D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000494:pharmacology; D006130:Growth Disorders / Q000097:blood / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007234:Infant, Premature / Q000097:blood / Q000254:growth & development*; D008297:Male; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C414620:fibroblast growth factor 21; D019382:Human Growth Hormone; D005346:Fibroblast Growth Factors