title: Genetic manipulation of the ghrelin signaling system in male mice reveals bone compartment specificity of acylated and unacylated ghrelin in the regulation of bone remodeling.
abstract: Ghrelin receptor-deficient (Ghsr-/-) mice that lack acylated ghrelin (AG) signaling retain a metabolic response to unacylated ghrelin (UAG). Recently, we showed that Ghsr-deficiency affects bone metabolism. The aim of this study was to further establish the impact of AG and UAG on bone metabolism. We compared bone metabolism in Ghsr-/- (lacking only AG signaling) and ghrelin-deficient (Ghrl-/-; both AG and UAG deficient) male mice. Ghrl-/- mice had lower cortical bone mass, whereas Ghsr-/- mice had lower trabecular bone mass. This demonstrates bone compartment-specific effects of AG and a role for UAG in bone metabolism. Also, Ghrl-/- but not Ghsr-/- mice had increased bone formation rate and increased osteogenic stem cell numbers in their bone marrow. In ex vivo bone marrow cultures both AG and UAG inhibited osteoblast differentiation. This indicated that bone resorption must be increased in these mice. Accordingly, osteoclastogenesis rate was faster in bone marrow cultures from Ghsr-/- and Ghrl-/- mice, and osteoclast formation was inhibited by AG signaling and partially suppressed by UAG. In osteoblast cultures, AG markedly induced osteoprotegerin gene expression and both peptides reduced RANKL/osteoprotegerin ratio. These data describe unique cell-type specific effects of AG and UAG within a single tissue, supporting a tight and complex control of bone formation and resorption as well as a link between nutrition and bone metabolism. The balance between AG and UAG actions in the bone marrow may lead to bone compartmental-specific effects.
authors: Department of Internal Medicine (P.J.D.D., M.V.D.V., B.C.J.V.D.E., J.M.M.G., A.-J.V.D.L., J.P.T.M.V.L.), Erasmus MC, Postbus 2040, 3000 CA Rotterdam, The Netherlands; United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center (Y.S.) and Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030; and Department of Metabolism and Aging (R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458.
authors: Patric J D
authors: PJ
authors: Delhanty
authors: Martijn
authors: M
authors: van der Velde
authors: Bram C J
authors: BC
authors: van der Eerden
authors: Yuxiang
authors: Y
authors: Sun
authors: Julia M M
authors: JM
authors: Geminn
authors: Aart-Jan
authors: AJ
authors: van der Lely
authors: Roy G
authors: RG
authors: Smith
authors: Johannes P T M
authors: JP
authors: van Leeuwen
mesh_terms: D000215:Acylation; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics*; D001842:Bone and Bones / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D054439:Ghrelin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054440:Receptors, Ghrelin / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin