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

• Published in: Endocrinology (Philadelphia) 2014-11, Vol.155 (11), p.4287-4295
• Main Authors: Delhanty, Patric J. D, van der Velde, Martijn, van der Eerden, Bram C. J, Sun, Yuxiang, Geminn, Julia M. M, van der Lely, Aart-Jan, Smith, Roy G, van Leeuwen, Johannes P. T. M
• Format: Article
• Language: English
• Subjects: Acylation; Animals; Bone and Bones - anatomy & histology; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Density - drug effects; Bone Density - genetics; Bone growth; Bone marrow; Bone mass; Bone remodeling; Bone Remodeling - drug effects; Bone Remodeling - genetics; Bone resorption; Bone turnover; Cancellous bone; Cell differentiation; Cells, Cultured; Cortical bone; Gene expression; Ghrelin; Ghrelin - genetics; Ghrelin - metabolism; Ghrelin - pharmacology; Male; Males; Metabolic response; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblastogenesis; Osteoblasts; Osteoclastogenesis; Osteogenesis; Osteoprotegerin; Peptides; Receptors, Ghrelin - genetics; Signal Transduction - genetics; Signalling systems; Stem cells; X-Ray Microtomography
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-2055

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.