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Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.

Nature communications (2014-10-22)
Johannes Keller, Philip Catala-Lehnen, Antje K Huebner, Anke Jeschke, Timo Heckt, Anja Lueth, Matthias Krause, Till Koehne, Joachim Albers, Jochen Schulze, Sarah Schilling, Michael Haberland, Hannah Denninger, Mona Neven, Irm Hermans-Borgmeyer, Thomas Streichert, Stefan Breer, Florian Barvencik, Bodo Levkau, Birgit Rathkolb, Eckhard Wolf, Julia Calzada-Wack, Frauke Neff, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabĕ de Angelis, Susanne Klutmann, Elena Tsourdi, Lorenz C Hofbauer, Burkhard Kleuser, Jerold Chun, Thorsten Schinke, Michael Amling
ABSTRACT

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

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