title: Liver-derived IGF-I is permissive for ovariectomy-induced trabecular bone loss.
abstract: BACKGROUND
  Estrogen deficiency results in trabecular bone loss, associated with T-cell proliferation in the bone marrow. Insulin-like growth factor I (IGF-I) is involved in the regulation of both bone metabolism and lymphopoiesis. A major part of serum IGF-I is derived from the liver. The aim of the present study was to investigate the role of liver-derived IGF-I for ovariectomy (ovx)-induced trabecular bone loss.
  
  
  METHODS
  Mice with adult liver-specific IGF-I inactivation (LI-IGF-I-/-) and wild type mice (WT) were either ovx or sham operated. After 5 weeks, the skeletal phenotype was analyzed by pQCT and microCT. The bone marrow cellularity was analyzed using FACS technique, and mRNA levels were quantified using real-time PCR.
  
  
  RESULTS
  Ovx resulted in a pronounced reduction in trabecular bone mineral density (-52%, P < 0.001), number (-45%, P < 0.01) and thickness (-13%, P < 0.01) in WT mice while these bone parameters were unaffected by ovx in LI-IGF-I-/- mice. Furthermore, ovx increased the number of T-cells in the bone marrow of the femur in WT but not in LI-IGF-I-/- mice. Interleukin 7 (IL-7) has been reported to stimulate the formation and function of osteoclasts by inducing the expression of receptor activator of NF-kappaB ligand (RANKL) on T-cells. IL-7 mRNA levels and the RANKL/osteoprotegerin ratio in bone were increased by ovx in WT but not in LI-IGF-I-/- mice.
  
  
  CONCLUSIONS
  Liver-derived IGF-I is permissive for ovx-induced trabecular bone loss. Our studies indicate that IGF-I might exert this permissive action by modulation of the number of T-cells and the expression of IL-7, which in turn is of importance for the RANKL/OPG ratio and consequently osteoclastogenesis in the bone marrow.
authors.affiliation: Center for Bone Research, Department of Internal Medicine, Div. of Endocrinology, Sahlgrenska Academy, Göteborg University, Bruna Stråket 16, 41345 Gothenburg, Sweden. Marie.Lindberg@medic.gu.se
authors.forename: M K
authors.initials: MK
authors.lastname: Lindberg
authors.forename: J
authors.initials: J
authors.lastname: Svensson
authors.forename: K
authors.initials: K
authors.lastname: Venken
authors.forename: T
authors.initials: T
authors.lastname: Chavoshi
authors.forename: N
authors.initials: N
authors.lastname: Andersson
authors.forename: S
authors.initials: S
authors.lastname: Movérare Skrtic
authors.forename: O
authors.initials: O
authors.lastname: Isaksson
authors.forename: D
authors.initials: D
authors.lastname: Vanderschueren
authors.forename: H
authors.initials: H
authors.lastname: Carlsten
authors.forename: C
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D005269:Femur / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010024:Osteoporosis / Q000209:etiology / Q000503:physiopathology*; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D013601:T-Lymphocytes / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D014057:Tomography, X-Ray Computed
chemical_list: D002352:Carrier Proteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D007334:Insulin-Like Growth Factor I; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase