title: Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1).
abstract: Calcium is a key component of the bone mineral hydroxyapatite. During osteoclast-mediated bone resorption, hydroxyapatite is dissolved and significant quantities of calcium are released. Several calcium transport systems have previously been identified in osteoclasts, including members of the sodium/calcium exchanger (NCX) family. Expression pattern and physiological role of NCX isoforms in osteoclasts, however, remain largely unknown at the moment. Our data indicate that all three NCX isoforms (NCX1, NCX2, and NCX3) are present in murine osteoclasts. RANKL-induced differentiation of murine osteoclast precursors into mature osteoclasts significantly attenuated the expression of NCX1, while NCX2 and NCX3 expressions were largely unaffected. To study the role of NCX1 during osteoclast differentiation and bone resorption, we crossed mice with exon 11 of the NCX1 gene flanked by loxP sites with cathepsin K-Cre transgenic mice. Mature osteoclasts derived from transgenic mice exhibited an 80-90% reduction of NCX1 protein. In vitro studies indicate that NCX1 is dispensable for osteoclast differentiation, but NCX1-deficient osteoclasts exhibited increased resorptive activity. In line with these in vitro findings, mice with an osteoclast-targeted deletion of the NCX1 gene locus displayed an age-dependent loss of bone mass. Thus, in summary, our data reveal NCX1 as a regulator of osteoclast-mediated bone resorption.
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, Bern University Hospital, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland.|Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.|NCCR Transcure, University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.|NCCR Kidney.CH, University of Zürich, Zürich, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Albano
authors.affiliation: NCCR Transcure, University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dolder
authors.affiliation: NCCR Transcure, University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Siegrist
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|NCCR Kidney.CH, University of Zürich, Zürich, Switzerland.
authors.forename: Annie
authors.initials: A
authors.lastname: Mercier-Zuber
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|NCCR Kidney.CH, University of Zürich, Zürich, Switzerland.
authors.forename: Muriel
authors.initials: M
authors.lastname: Auberson
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|NCCR Kidney.CH, University of Zürich, Zürich, Switzerland.
authors.forename: Candice
authors.initials: C
authors.lastname: Stoudmann
authors.affiliation: NCCR Transcure, University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Willy
authors.initials: W
authors.lastname: Hofstetter
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|NCCR Kidney.CH, University of Zürich, Zürich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, Bern University Hospital, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland. Daniel.Fuster@ibmm.unibe.ch.|Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland. Daniel.Fuster@ibmm.unibe.ch.|NCCR Transcure, University of Bern, Bern, Switzerland. Daniel.Fuster@ibmm.unibe.ch.|Department of Clinical Research, University of Bern, Bern, Switzerland. Daniel.Fuster@ibmm.unibe.ch.|NCCR Kidney.CH, University of Zürich, Zürich, Switzerland. Daniel.Fuster@ibmm.unibe.ch.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fuster
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism*
chemical_list: C499849:NCX1 protein, mouse; D020033:Protein Isoforms; D053245:RANK Ligand; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium
keywords: Bone; NCX1; Osteoclast; Sodium/calcium exchanger