title: The biologics anakinra and etanercept prevent cytokine-induced growth retardation in cultured fetal rat metatarsal bones.
abstract: OBJECTIVE
  Chronic inflammation during childhood often leads to impaired bone growth and reduced adult height. Proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α synergistically impair bone growth in vitro. We hypothesized that biologic agents may rescue bones from cytokine-induced growth impairment and that insulin growth factor (IGF)-I may potentiate such an effect.
  
  
  METHODS
  Metatarsal bones from fetal Sprague-Dawley rats (19-20 days p.c.) were treated with IL-1β plus TNF-α, or the combination of these cytokines with anakinra (IL-1 receptor antagonist), etanercept (TNF-inhibitor) and/or IGF-I. The bones were measured and growth expressed as percent increase in bone length over the 7-day culture period.
  
  
  RESULTS
  When exposed to IL-1β plus TNF-α (10 + 10 ng/ml), bone growth was markedly suppressed (6.6 ± 1.4 vs. 50.6 ± 2.5% in control bones; p < 0.001). The growth of cytokine exposed bones (IL-1β plus TNF-α) was dose-dependently rescued by anakinra (0.05-500 μg/ml) or etanercept (0.5-500 μg/ml); at the highest concentrations, growth was similar as in control bones never exposed to cytokines. Also when combining IGF-I (100 ng/ml) and relatively low concentrations of anakinra (0.05 μg/ml) or etanercept (5 μg/ml), growth was rescued in an additive way.
  
  
  CONCLUSIONS
  Etanercept and anakinra efficiently and dose-dependently prevent cytokine-induced bone growth impairment, and combination with IGF-I further improves bone growth.
authors.affiliation: Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. paofer@ki.se
authors.forename: Paola
authors.initials: P
authors.lastname: Fernandez-Vojvodich
authors.forename: Elham
authors.initials: E
authors.lastname: Karimian
authors.forename: Lars
authors.initials: L
authors.lastname: Sävendahl
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D016207:Cytokines / Q000494:pharmacology*; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008682:Metatarsal Bones / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D000068800:Etanercept