title: Targeting the lateral but not the third ventricle induces bone loss in ewe: an experimental approach to generate an improved large animal model of osteoporosis.
abstract: BACKGROUND
  Osteoporosis is a chronic disease characterized by bone loss and increased skeletal fragility. Large animal models are required for preclinical testing of new therapeutic approaches. We have recently demonstrated that continuous intracerebroventricular (ICV) application of leptin into the lateral ventricle (LV) induces bone loss in ewe. On the basis of these findings, we reasoned that the third ventricle (TV) is an even better target because of its closer location to the hypothalamus that mediates leptin effects on bone.
  
  
  METHODS
  Corriedale sheep were randomly mixed to four groups of four ewe each: control entire (control), ovarectomy plus ICV application of cerebrospinal fluid (OVX), OVX plus ICV application of leptin into the LV (leptin-LV); and ICV application of leptin into the TV (leptin-TV). After 3 months, histomorphometric characterization and bone turnover parameters were analyzed.
  
  
  RESULTS
  Highly significant loss of trabecular bone was observed only in leptin-LV group. Increased osteoclast indices and urinary cross-lap excretion were observed in OVX and leptin-TV group. In contrast, serum parameters of osteoblast activity were only significantly decreased in leptin-LV group. Autopsy of ewe brain showed fibrosis around the stainless steel cannula in leptin-TV group.
  
  
  CONCLUSIONS
  ICV application of leptin into the LV strongly reduces bone formation and leads to a highly significant trabecular bone loss in ewe. In contrast, ICV application of leptin into the TV is technically more demanding and results are unpredictable, because the required use of stainless steel cannula induces peri-implant fibrosis that might prevent leptin to enter the cerebrospinal fluid.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Oheim
authors.forename: Frank Timo
authors.initials: FT
authors.lastname: Beil
authors.forename: Florian
authors.initials: F
authors.lastname: Barvencik
authors.forename: Marcus
authors.initials: M
authors.lastname: Egermann
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Clarke
authors.forename: Pia
authors.initials: P
authors.lastname: Pogoda
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000139:chemically induced / Q000150:complications* / Q000175:diagnosis; D004195:Disease Models, Animal; D005260:Female; D007276:Injections, Intraventricular; D020547:Lateral Ventricles / Q000002:abnormalities* / Q000187:drug effects; D020738:Leptin / Q000008:administration & dosage / Q000633:toxicity; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D011379:Prognosis; D012756:Sheep; D020542:Third Ventricle
chemical_list: D020738:Leptin