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

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 Hrab[ebreve] de Angelis, Susanne Klutmann, Elena Tsourdi, Lorenz C. Hofbauer, Burkhard Kleuser, Jerold Chun, Thorsten Schinke and Michael Amling ()
Additional contact information
Johannes Keller: University Medical Center Hamburg-Eppendorf
Philip Catala-Lehnen: University Medical Center Hamburg-Eppendorf
Antje K. Huebner: University Medical Center Hamburg-Eppendorf
Anke Jeschke: University Medical Center Hamburg-Eppendorf
Timo Heckt: University Medical Center Hamburg-Eppendorf
Anja Lueth: Institute of Nutritional Science, University of Potsdam
Matthias Krause: University Medical Center Hamburg-Eppendorf
Till Koehne: University Medical Center Hamburg-Eppendorf
Joachim Albers: University Medical Center Hamburg-Eppendorf
Jochen Schulze: University Medical Center Hamburg-Eppendorf
Sarah Schilling: University Medical Center Hamburg-Eppendorf
Michael Haberland: University Medical Center Hamburg-Eppendorf
Hannah Denninger: University Medical Center Hamburg-Eppendorf
Mona Neven: University Medical Center Hamburg-Eppendorf
Irm Hermans-Borgmeyer: Center for Molecular Neurobiology, University of Hamburg
Thomas Streichert: Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf
Stefan Breer: University Medical Center Hamburg-Eppendorf
Florian Barvencik: University Medical Center Hamburg-Eppendorf
Bodo Levkau: Institute of Pathophysiology, University Hospital Essen
Birgit Rathkolb: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University
Eckhard Wolf: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University
Julia Calzada-Wack: German Mouse Clinic, Institute of Pathology, Helmholtz Center Munich
Frauke Neff: German Mouse Clinic, Institute of Pathology, Helmholtz Center Munich
Valerie Gailus-Durner: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Helmut Fuchs: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Martin Hrab[ebreve] de Angelis: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich
Susanne Klutmann: University Medical Center Hamburg-Eppendorf
Elena Tsourdi: Dresden University Medical Center
Lorenz C. Hofbauer: Dresden University Medical Center
Burkhard Kleuser: Institute of Nutritional Science, University of Potsdam
Jerold Chun: Scripps Research Institute
Thorsten Schinke: University Medical Center Hamburg-Eppendorf
Michael Amling: University Medical Center Hamburg-Eppendorf

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6215

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