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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

Author
item DELHANTY, PATRIC J - Erasmus Medical Center
item VAN DER VELDE, MARTIJN - Erasmus Medical Center
item VAN DER EERDEN, BRAN C - Erasmus Medical Center
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)
item GEMINN, JULIA M - Erasmus Medical Center
item VAN DER LELY, AART-JAN - Erasmus Medical Center
item SMITH, ROY - Scripps Institute
item VAN LEEUWEN, JOHANNES PT - Erasmus Medical Center

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/19/2014
Publication Date: 11/1/2014
Citation: Delhanty, P.D., Van Der Velde, M., Van Der Eerden, B.J., Sun, Y., Geminn, J.M., Van Der Lely, A., Smith, R.G., Van Leeuwen, J.M. 2014. 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. Endocrinology. 155(11):4287-4295.

Interpretive Summary: The gut hormone ghrelin's effect is mediated by its receptor (GHS-R). Ghrelin-deficient mice lack both acylated ghrelin (AG) and unacylated ghrelin (UAG). In contrast, ghrelin receptor- deficient mice (lacking the gene for GHS-R) block only the effect of AG, but not the effect of UAG. We have shown that ghrelin receptor-deficiency affects bone metabolism. This study was to further establish the impact of AG and UAG on bone metabolism. We compared bone metabolism in ghrelin receptor-deficient mice (lacking activation only by AG) and ghrelin-deficient (lacking both AG and UAG) mice. We have observed different characteristics in ghrelin-deficient and ghrelin receptor-deficient mice. This study suggests that AG, UAG, and GHS-R play an important role in bone metabolism, and that deletion of any component of this system may affect bone structure. Further studies would be beneficial for fully exploring the therapeutic potential of AG and UAG for bone health.

Technical 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.