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dc.contributor.author
Davis, Hannah M.
dc.contributor.author
Pacheco Costa, Rafael
dc.contributor.author
Atkinson, Emily G.
dc.contributor.author
Brun, Lucas Ricardo Martín
dc.contributor.author
Gortazar, Arancha R.
dc.contributor.author
Harris, Julia
dc.contributor.author
Hiasa, Masahiro
dc.contributor.author
Bolarinwa, Surajudeen A.
dc.contributor.author
Yoneda, Toshiyuki
dc.contributor.author
Ivan, Mircea
dc.contributor.author
Bruzzaniti, Angela
dc.contributor.author
Bellido, Teresita
dc.contributor.author
Plotkin, Lilian I.
dc.date.available
2018-07-30T15:50:46Z
dc.date.issued
2017-06
dc.identifier.citation
Davis, Hannah M.; Pacheco Costa, Rafael; Atkinson, Emily G.; Brun, Lucas Ricardo Martín; Gortazar, Arancha R.; et al.; Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging; Wiley Blackwell Publishing, Inc; Aging Cell; 16; 3; 6-2017; 551-563
dc.identifier.issn
1474-9718
dc.identifier.uri
http://hdl.handle.net/11336/53391
dc.description.abstract
Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Wiley Blackwell Publishing, Inc
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
Aging
dc.subject
Apoptosis
dc.subject
Connexin43
dc.subject
Hmgb1
dc.subject
Mir21
dc.subject
Osteocyte
dc.subject.classification
Inmunología
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-07-30T13:49:39Z
dc.identifier.eissn
1474-9726
dc.journal.volume
16
dc.journal.number
3
dc.journal.pagination
551-563
dc.journal.pais
Reino Unido
dc.journal.ciudad
Londres
dc.description.fil
Fil: Davis, Hannah M.. Indiana University; Estados Unidos
dc.description.fil
Fil: Pacheco Costa, Rafael. Indiana University; Estados Unidos
dc.description.fil
Fil: Atkinson, Emily G.. Indiana University; Estados Unidos
dc.description.fil
Fil: Brun, Lucas Ricardo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Indiana University; Estados Unidos
dc.description.fil
Fil: Gortazar, Arancha R.. Universidad San Pablo; España
dc.description.fil
Fil: Harris, Julia. Indiana University; Estados Unidos
dc.description.fil
Fil: Hiasa, Masahiro. Indiana University; Estados Unidos
dc.description.fil
Fil: Bolarinwa, Surajudeen A.. Indiana University; Estados Unidos
dc.description.fil
Fil: Yoneda, Toshiyuki. Indiana University; Estados Unidos
dc.description.fil
Fil: Ivan, Mircea. Indiana University; Estados Unidos
dc.description.fil
Fil: Bruzzaniti, Angela. Indiana University; Estados Unidos
dc.description.fil
Fil: Bellido, Teresita. Indiana University; Estados Unidos
dc.description.fil
Fil: Plotkin, Lilian I.. Indiana University; Estados Unidos
dc.journal.title
Aging Cell
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1111/acel.12586
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12586
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