High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

Página do item simplificado
dc.contributor.authorCosta, Rafael Pacheco da [UNIFESP]
dc.contributor.authorHassan, Iraj
dc.contributor.authorReginato, Rejane Daniele [UNIFESP]
dc.contributor.authorDavis, Hannah M.
dc.contributor.authorBruzzaniti, Angela
dc.contributor.authorAllen, Matthew R.
dc.contributor.authorPlotkin, Lilian I.
dc.contributor.institutionIndiana Univ Sch Med
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionIndiana Univ
dc.date.accessioned2016-01-24T14:35:27Z
dc.date.available2016-01-24T14:35:27Z
dc.date.issued2014-03-21
dc.description.abstractBackground: Connexin proteins are essential for cell differentiation, function, and survival. Results: Global deletion of Cx37 results in increased bone mass caused by reduced osteoclast maturation. Conclusion: Our findings demonstrate a previously unrecognized role of Cx37 in bone homeostasis in vivo. Significance: Therapeutic approaches to increase bone mass might be developed by interfering with Cx37 function.Connexin (Cx) proteins are essential for cell differentiation, function, and survival in all tissues with Cx43 being the most studied in bone. We now report that Cx37, another member of the connexin family of proteins, is expressed in osteoclasts, osteoblasts, and osteocytes. Mice with global deletion of Cx37 (Cx37(-/-)) exhibit higher bone mineral density, cancellous bone volume, and mechanical strength compared with wild type littermates. Osteoclast number and surface are significantly lower in bone of Cx37(-/-) mice. in contrast, osteoblast number and surface and bone formation rate in bones from Cx37(-/-) mice are unchanged. Moreover, markers of osteoblast activity ex vivo and in vivo are similar to those of Cx37(+/+) littermates. sRANKL/M-CSF treatment of nonadherent Cx37(-/-) bone marrow cells rendered a 5-fold lower level of osteoclast differentiation compared with Cx37(+/+) cell cultures. Further, Cx37(-/-) osteoclasts are smaller and have fewer nuclei per cell. Expression of RANK, TRAP, cathepsin K, calcitonin receptor, matrix metalloproteinase 9, NFATc1, DC-STAMP, ATP6v0d1, and CD44, markers of osteoclast number, fusion, or activity, is lower in Cx37(-/-) osteoclasts compared with controls. in addition, nonadherent bone marrow cells from Cx37(-/-) mice exhibit higher levels of markers for osteoclast precursors, suggesting altered osteoclast differentiation. the reduction of osteoclast differentiation is associated with activation of Notch signaling. We conclude that Cx37 is required for osteoclast differentiation and fusion, and its absence leads to arrested osteoclast maturation and high bone mass in mice. These findings demonstrate a previously unrecognized role of Cx37 in bone homeostasis that is not compensated for by Cx43 in vivo.en
dc.description.affiliationIndiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, in 46202 USA
dc.description.affiliationUniversidade Federal de São Paulo, Sch Med, Dept Morphol & Genet, BR-04023 São Paulo, Brazil
dc.description.affiliationIndiana Univ, Sch Dent, Dept Oral Biol, Indianapolis, in 46202 USA
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Sch Med, Dept Morphol & Genet, BR-04023 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipNational Institutes of Health
dc.description.sponsorshipClinical and Transitional Sciences Institute Project Development Team (PDT) from Indiana University
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipRonald E. McNair Post-baccalaureate Achievement Program from the U.S. Dept. of Education
dc.description.sponsorshipClinical and Transitional Sciences Institute Award
dc.description.sponsorshipIDNational Institutes of Health: R01-AR053643
dc.description.sponsorshipIDNational Institutes of Health: S10-RR023710
dc.description.sponsorshipIDClinical and Transitional Sciences Institute Project Development Team (PDT) from Indiana University: TR000006
dc.description.sponsorshipIDCAPES: 1065/11-4
dc.format.extent8508-8520
dc.identifierhttp://dx.doi.org/10.1074/jbc.M113.529735
dc.identifier.citationJournal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 289, n. 12, p. 8508-8520, 2014.
dc.identifier.doi10.1074/jbc.M113.529735
dc.identifier.issn0021-9258
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/37554
dc.identifier.wosWOS:000333157500042
dc.language.isoeng
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.relation.ispartofJournal of Biological Chemistry
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectBoneen
dc.subjectGap Junctionsen
dc.subjectOsteoblastsen
dc.subjectOsteoclasten
dc.subjectOsteocyteen
dc.subjectCx37en
dc.titleHigh Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiationen
dc.typeinfo:eu-repo/semantics/article
Arquivos
Coleções
EPM - Artigos