title: Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.
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.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Keller
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Catala-Lehnen
authors.affiliation: 1] Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany [2] Institute of Human Genetics, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Jeschke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Heckt
authors.affiliation: Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Lueth
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Krause
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Koehne
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Albers
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulze
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schilling
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Haberland
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Denninger
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Neven
authors.affiliation: Center for Molecular Neurobiology, University of Hamburg, 20251 Hamburg, Germany.
authors.forename: Irm
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.affiliation: Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Breer
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Barvencik
authors.affiliation: Institute of Pathophysiology, University Hospital Essen, 45122 Essen, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.affiliation: 1] Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University, 81377 Munich, Germany [2] German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilian-University, 81377 Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: German Mouse Clinic, Institute of Pathology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.affiliation: German Mouse Clinic, Institute of Pathology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: 1] German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany [2] Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany [3] German Center for Diabetes Research, 85764 Neuherberg, Germany.
authors.forename: Martin Hrabĕ
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Klutmann
authors.affiliation: Department of Medicine III, Dresden University Medical Center, 01307 Dresden, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Tsourdi
authors.affiliation: Department of Medicine III, Dresden University Medical Center, 01307 Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.affiliation: Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Scripps Research Institute, La Jolla, California 92937, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
mesh_terms: D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002116:Calcitonin / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology*; D010012:Osteogenesis; D010024:Osteoporosis / Q000503:physiopathology; D010641:Phenotype; D016062:Porosity; D018003:Receptors, Calcitonin / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D018003:Receptors, Calcitonin; C060506:sphingosine 1-phosphate; D002116:Calcitonin; D017364:Collagenases; D013110:Sphingosine