Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid

ABSTRACT: Bone is a dynamic tissue with constant adaptative physiological changes in its homeostasis through life called bone modeling and remodeling. These processes enable to achieve a balance between bone formation and bone resorption at any particular age. These processes involve the activity of...

Full description

Autores:
Vargas Franco, Jorge William
Tipo de recurso:
Doctoral thesis
Fecha de publicación:
2019
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
eng
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/13851
Acceso en línea:
http://hdl.handle.net/10495/13851
Palabra clave:
Zoledronic acid
Ácido zoledrónico
Ligando RANK
RANK ligand
Growing skeleton
Craniofacial skeleton
RANKL/RANK/OPG
N-BPs
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 2.5 Colombia (CC BY-NC-ND 2.5 CO)
id UDEA2_94720bebdd7119bae2cdf0aac164bcf4
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/13851
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
title Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
spellingShingle Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
Zoledronic acid
Ácido zoledrónico
Ligando RANK
RANK ligand
Growing skeleton
Craniofacial skeleton
RANKL/RANK/OPG
N-BPs
title_short Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
title_full Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
title_fullStr Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
title_full_unstemmed Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
title_sort Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acid
dc.creator.fl_str_mv Vargas Franco, Jorge William
dc.contributor.advisor.none.fl_str_mv Lézot, Frédéric
Gómez Gil, David Francisco
dc.contributor.author.none.fl_str_mv Vargas Franco, Jorge William
dc.subject.decs.none.fl_str_mv Zoledronic acid
Ácido zoledrónico
Ligando RANK
RANK ligand
topic Zoledronic acid
Ácido zoledrónico
Ligando RANK
RANK ligand
Growing skeleton
Craniofacial skeleton
RANKL/RANK/OPG
N-BPs
dc.subject.proposal.spa.fl_str_mv Growing skeleton
Craniofacial skeleton
RANKL/RANK/OPG
N-BPs
description ABSTRACT: Bone is a dynamic tissue with constant adaptative physiological changes in its homeostasis through life called bone modeling and remodeling. These processes enable to achieve a balance between bone formation and bone resorption at any particular age. These processes involve the activity of distinct types of cells namely chondroblasts, osteocytes, osteoblasts, bone lining cells and osteoclasts. The role of the osteoclasts has been deeply analyzed in endochondral ossification during development and growth, and in adulthood throughout bone remodeling. Osteoclast differentiation requires two essential factors named macrophage colony stimulating factor (M-CSF), acting on its receptor c-FMS, and receptor activator of nuclear factor-κB ligand (RANKL), acting on its main receptor RANK which binding is modulated by the decoy receptor osteoprotegerin (OPG). M-CSF is involved in the osteoclastogenesis process mainly by promoting the proliferation and survival of osteoclast precursors. RANKL functions as the primary factor driving differentiation of osteoclasts precursors into ostéoclasts, as well as in their maturation and activity. Any imbalances between bone formation and resorption secondary to osteoclasts alterations lead to pathologies that could appear either in childhood or adulthood. Those pathologies are known as osteopetrotic and osteolytic diseases. Osteopetrotic disease group is related to a greater bone apposition, resulting in a bone mass increased, mainly due to osteoclasts dysfunction or absence. The osteolytic disease group, on the contrary, is related to an increase in bone turnover associated to an increase in osteoclasts number or/and activity. Osteolytic diseases are so characterized by a negative balance between bone formation and resorption. Osteolytic diseases generate a low bone density and a deterioration of bone microarchitecture, leading towards a weak bone phenotype and a higher fracture risk. These pathologies have different etiologies and affect both children and adults. Osteolytic diseases affecting children include an inherited group of rare disorders and can be divided into two types, early and late, depending on the timing of the osteoporotic onset. Early-onset osteoporosis is related to genetic mutations and appears soon after birth. Late-onset forms are related with hypercalcemic disorders (hyperparathyroidism, vitamin D-related causes, malignancy, medications, endocrine disorders, genetic disorders, and miscellaneous causes). In adults, osteolytic diseases include primary (or age-related) osteoporosis that is the most common form with two types. The first is associated with estrogen deficiency at menopause and the second related to long-term remodeling inefficiency. Secondary osteoporosis could appear in the context of endocrine, reproductive, gastrointestinal and nutritional disorders, following treatments with drugs like glucocorticoids and anti-convulsants, in the case of Paget disease, in the presence of malignant primary bone tumors or associated with bone metastases of other cancers as breast and prostate cancers.
publishDate 2019
dc.date.issued.none.fl_str_mv 2019
dc.date.accessioned.none.fl_str_mv 2020-04-11T18:17:46Z
dc.date.available.none.fl_str_mv 2020-04-11T18:17:46Z
dc.type.spa.fl_str_mv info:eu-repo/semantics/doctoralThesis
dc.type.hasversion.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
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dc.type.redcol.spa.fl_str_mv https://purl.org/redcol/resource_type/TD
dc.type.local.spa.fl_str_mv Tesis/Trabajo de grado - Monografía - Doctorado
format http://purl.org/coar/resource_type/c_db06
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dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/10495/13851
url http://hdl.handle.net/10495/13851
dc.language.iso.spa.fl_str_mv eng
language eng
dc.rights.spa.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.*.fl_str_mv Atribución-NoComercial-SinDerivadas 2.5 Colombia (CC BY-NC-ND 2.5 CO)
dc.rights.uri.*.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/co/
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dc.rights.creativecommons.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 2.5 Colombia (CC BY-NC-ND 2.5 CO)
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http://purl.org/coar/access_right/c_abf2
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dc.format.extent.spa.fl_str_mv 239
dc.format.mimetype.spa.fl_str_mv application/pdf
institution Universidad de Antioquia
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spelling Lézot, FrédéricGómez Gil, David FranciscoVargas Franco, Jorge William2020-04-11T18:17:46Z2020-04-11T18:17:46Z2019http://hdl.handle.net/10495/13851ABSTRACT: Bone is a dynamic tissue with constant adaptative physiological changes in its homeostasis through life called bone modeling and remodeling. These processes enable to achieve a balance between bone formation and bone resorption at any particular age. These processes involve the activity of distinct types of cells namely chondroblasts, osteocytes, osteoblasts, bone lining cells and osteoclasts. The role of the osteoclasts has been deeply analyzed in endochondral ossification during development and growth, and in adulthood throughout bone remodeling. Osteoclast differentiation requires two essential factors named macrophage colony stimulating factor (M-CSF), acting on its receptor c-FMS, and receptor activator of nuclear factor-κB ligand (RANKL), acting on its main receptor RANK which binding is modulated by the decoy receptor osteoprotegerin (OPG). M-CSF is involved in the osteoclastogenesis process mainly by promoting the proliferation and survival of osteoclast precursors. RANKL functions as the primary factor driving differentiation of osteoclasts precursors into ostéoclasts, as well as in their maturation and activity. Any imbalances between bone formation and resorption secondary to osteoclasts alterations lead to pathologies that could appear either in childhood or adulthood. Those pathologies are known as osteopetrotic and osteolytic diseases. Osteopetrotic disease group is related to a greater bone apposition, resulting in a bone mass increased, mainly due to osteoclasts dysfunction or absence. The osteolytic disease group, on the contrary, is related to an increase in bone turnover associated to an increase in osteoclasts number or/and activity. Osteolytic diseases are so characterized by a negative balance between bone formation and resorption. Osteolytic diseases generate a low bone density and a deterioration of bone microarchitecture, leading towards a weak bone phenotype and a higher fracture risk. These pathologies have different etiologies and affect both children and adults. Osteolytic diseases affecting children include an inherited group of rare disorders and can be divided into two types, early and late, depending on the timing of the osteoporotic onset. Early-onset osteoporosis is related to genetic mutations and appears soon after birth. Late-onset forms are related with hypercalcemic disorders (hyperparathyroidism, vitamin D-related causes, malignancy, medications, endocrine disorders, genetic disorders, and miscellaneous causes). In adults, osteolytic diseases include primary (or age-related) osteoporosis that is the most common form with two types. The first is associated with estrogen deficiency at menopause and the second related to long-term remodeling inefficiency. Secondary osteoporosis could appear in the context of endocrine, reproductive, gastrointestinal and nutritional disorders, following treatments with drugs like glucocorticoids and anti-convulsants, in the case of Paget disease, in the presence of malignant primary bone tumors or associated with bone metastases of other cancers as breast and prostate cancers.RESUMEN: El hueso es un tejido dinámico, sometido a constantes cambios fisiológicos adaptativos para mantener su homeostasis presente a lo largo de la vida, estos procesos se denominan modelado y remodelado óseo. Con ellos se busca, tanto en la niñez como en la edad adulta, lograr un equilibrio entre la formación ósea y la resorción ósea. Para el adecuado desarrollo de estos procesos se requiere la participación de distintos tipos de células como los condroblastos, los osteocitos, los osteoblastos, las células de revestimiento óseo y osteoclastos. El papel de los osteoclastos ha sido analizado ampliamente tanto en la osificación endocondral, durante el desarrollo y el crecimiento, y en la edad adulta durante la remodelación ósea. El proceso de diferenciación osteoclastica requiere dos factores esenciales llamados factor estimulante de colonias de macrófagos (M-CSF), que actúa sobre su receptor c-FMS, y el ligando activador del receptor del factor nuclear-κB (RANKL), que actúa sobre su receptor principal RANK y cuya unión es modulada por la osteoprotegerina (OPG), actuando como un receptor señuelo, para controlar su actividad. El M-CSF está involucrado en el proceso de osteoclastogénesis principalmente promoviendo la proliferación y supervivencia de los precursores osteoclásticos. Por su parte RANKL funciona como el factor principal que impulsa la diferenciación de los precursores osteoclásticos en osteoclastos, favoreciendo también su maduración y actividad. Desbalances entre la formación de hueso y la reabsorción, secundaria a alteraciones en la actividad de los osteoclastos, conducen a patologías osteoliticas que pueden aparecer en la infancia o la edad adulta y que se han conocido como enfermedades osteopetróticas y/o enfermedades osteolíticas. Las enfermedades del tipo osteopetrótico están relacionadas con una mayor aposición ósea debido a la disfunción o ausencia de osteoclastos, dando como resultado un aumento de la masa ósea. Por el contrario, las enfermedades del tipo osteolíticas, se deben a un aumento en el recambio óseo y están asociadas a un aumento en el número o Actividad de los osteoclastos, se caracterizan por un equilibrio negativo entre la formación y resorción ósea. Estas enfermedades osteoliticas generan una baja densidad y un deterioro de la microarquitectura ósea, lo que conduce a un fenotipo óseo débil con un mayor riesgo de fractura. La etiología de estas patologías es diversa y se considera que pueden afectar tanto a niños como a adultos. Dentro de las osteolisis que afectan a los niños se incluyen un grupo trastornos raros de tipo hereditario, que se dividen en temprano y tardío según el periodo de inicio. La osteoporosis de inicio temprano está relacionada con mutaciones genéticas y aparecen poco después del nacimiento. Las formas de inicio tardío están relacionadas con trastornos hipercalcémicos (hiperparatiroidismo, causas relacionadas con la vitamina D, malignidad, medicamentos, trastornos endocrinos, trastornos genéticos y causas diversas). En los adultos, las enfermedades osteolíticas incluyen osteoporosis primaria (o relacionada con la edad) que es la forma más común y que ha sido asociada con dos tipos diferentes: el primero está asociado con la deficiencia de estrógenos en la menopausia y el segundo relacionado con la ineficiencia de remodelación a largo plazo. La osteoporosis secundaria en los adultos se ha relacionado con trastornos endocrinos, reproductivos, gastrointestinales y nutricionales, posterior a tratamientos con medicamentos como glucocorticoides y anticonvulsivos, en el caso de la enfermedad de Paget, en presencia de tumores óseos primarios malignos o asociados con metástasis óseas de otros cánceres como los de mama y próstata.239application/pdfenginfo:eu-repo/semantics/acceptedVersioninfo:eu-repo/semantics/doctoralThesishttp://purl.org/coar/resource_type/c_db06https://purl.org/redcol/resource_type/TDTesis/Trabajo de grado - Monografía - Doctoradoinfo:eu-repo/semantics/openAccessAtribución-NoComercial-SinDerivadas 2.5 Colombia (CC BY-NC-ND 2.5 CO)https://creativecommons.org/licenses/by-nc-nd/2.5/co/http://purl.org/coar/access_right/c_abf2https://creativecommons.org/licenses/by-nc-nd/4.0/Impacts on the growing and adult skeleton of different genetically-achieved RANKL activity levels, consequences on the response to zoledronic acidZoledronic acidÁcido zoledrónicoLigando RANKRANK ligandGrowing skeletonCraniofacial skeletonRANKL/RANK/OPGN-BPsDoctor en Ciencias OdontológicasPh.D. in Molecular and Cellular BiologyDoctoradoFacultad de Odontología. Doctorado en Ciencias OdontológicasSarcomes osseuxe et remodelage des tissus calcifiés. Carrera Ph.D. degree in Molecular and cellular biologyUniversidad de AntioquiaUniversité de NantesCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8823https://bibliotecadigital.udea.edu.co/bitstream/10495/13851/2/license_rdfb88b088d9957e670ce3b3fbe2eedbc13MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://bibliotecadigital.udea.edu.co/bitstream/10495/13851/3/license.txt8a4605be74aa9ea9d79846c1fba20a33MD53ORIGINALVargasFrancoJorge_2019_ GrowingAdultSkeletonRANKLActivity.pdfVargasFrancoJorge_2019_ GrowingAdultSkeletonRANKLActivity.pdfTesis doctoralapplication/pdf8042921https://bibliotecadigital.udea.edu.co/bitstream/10495/13851/4/VargasFrancoJorge_2019_%20GrowingAdultSkeletonRANKLActivity.pdf205fe076051c5816a783cf93e61cfb12MD5410495/13851oai:bibliotecadigital.udea.edu.co:10495/138512022-08-02 17:31:41.824Repositorio Institucional Universidad de Antioquiaandres.perez@udea.edu.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