Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways

Autores
Lezcano, Virginia Alicia; Bellido, T.; Plotkin, L. I.; Boland, Ricardo Leopoldo; Morelli, Susana Ana
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [3H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na3VO4 increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.
Fil: Lezcano, Virginia Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Bellido, T.. Indiana University; Estados Unidos
Fil: Plotkin, L. I.. Indiana University; Estados Unidos
Fil: Boland, Ricardo Leopoldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Morelli, Susana Ana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Materia
AF-ALN UPTAKE
BISPHOSPHONATES
CX43 HEMICHANNELS
OSTEOBLAST SURVIVAL
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/60655
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/60655
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathwaysLezcano, Virginia AliciaBellido, T.Plotkin, L. I.Boland, Ricardo LeopoldoMorelli, Susana AnaAF-ALN UPTAKEBISPHOSPHONATESCX43 HEMICHANNELSOSTEOBLAST SURVIVALhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [3H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na3VO4 increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.Fil: Lezcano, Virginia Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Bellido, T.. Indiana University; Estados UnidosFil: Plotkin, L. I.. Indiana University; Estados UnidosFil: Boland, Ricardo Leopoldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Morelli, Susana Ana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaElsevier Science Inc2012-02-15info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/60655Lezcano, Virginia Alicia; Bellido, T.; Plotkin, L. I.; Boland, Ricardo Leopoldo; Morelli, Susana Ana; Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways; Elsevier Science Inc; Archives of Biochemistry and Biophysics; 518; 2; 15-2-2012; 95-1020003-9861CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0003986111004346info:eu-repo/semantics/altIdentifier/doi/10.1016/j.abb.2011.12.022info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804299/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:18Zoai:ri.conicet.gov.ar:11336/60655instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:58:18.478CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
title Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
spellingShingle Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
Lezcano, Virginia Alicia
AF-ALN UPTAKE
BISPHOSPHONATES
CX43 HEMICHANNELS
OSTEOBLAST SURVIVAL
title_short Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
title_full Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
title_fullStr Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
title_full_unstemmed Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
title_sort Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
dc.creator.none.fl_str_mv Lezcano, Virginia Alicia
Bellido, T.
Plotkin, L. I.
Boland, Ricardo Leopoldo
Morelli, Susana Ana
author Lezcano, Virginia Alicia
author_facet Lezcano, Virginia Alicia
Bellido, T.
Plotkin, L. I.
Boland, Ricardo Leopoldo
Morelli, Susana Ana
author_role author
author2 Bellido, T.
Plotkin, L. I.
Boland, Ricardo Leopoldo
Morelli, Susana Ana
author2_role author
author
author
author
dc.subject.none.fl_str_mv AF-ALN UPTAKE
BISPHOSPHONATES
CX43 HEMICHANNELS
OSTEOBLAST SURVIVAL
topic AF-ALN UPTAKE
BISPHOSPHONATES
CX43 HEMICHANNELS
OSTEOBLAST SURVIVAL
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [3H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na3VO4 increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.
Fil: Lezcano, Virginia Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Bellido, T.. Indiana University; Estados Unidos
Fil: Plotkin, L. I.. Indiana University; Estados Unidos
Fil: Boland, Ricardo Leopoldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Morelli, Susana Ana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
description Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [3H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na3VO4 increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents.
publishDate 2012
dc.date.none.fl_str_mv 2012-02-15
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/60655
Lezcano, Virginia Alicia; Bellido, T.; Plotkin, L. I.; Boland, Ricardo Leopoldo; Morelli, Susana Ana; Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways; Elsevier Science Inc; Archives of Biochemistry and Biophysics; 518; 2; 15-2-2012; 95-102
0003-9861
CONICET Digital
CONICET
url http://hdl.handle.net/11336/60655
identifier_str_mv Lezcano, Virginia Alicia; Bellido, T.; Plotkin, L. I.; Boland, Ricardo Leopoldo; Morelli, Susana Ana; Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways; Elsevier Science Inc; Archives of Biochemistry and Biophysics; 518; 2; 15-2-2012; 95-102
0003-9861
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0003986111004346
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.abb.2011.12.022
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804299/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science Inc
publisher.none.fl_str_mv Elsevier Science Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.885934

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