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Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence

In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical...

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Autores principales: Kim, Ha-Neui, Xiong, Jinhu, MacLeod, Ryan S., Iyer, Srividhya, Fujiwara, Yuko, Cawley, Keisha M., Han, Li, He, Yonghan, Thostenson, Jeff D., Ferreira, Elisabeth, Jilka, Robert L., Zhou, Daohong, Almeida, Maria, O’Brien, Charles A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566701/
https://www.ncbi.nlm.nih.gov/pubmed/32870816
http://dx.doi.org/10.1172/jci.insight.138815
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author Kim, Ha-Neui
Xiong, Jinhu
MacLeod, Ryan S.
Iyer, Srividhya
Fujiwara, Yuko
Cawley, Keisha M.
Han, Li
He, Yonghan
Thostenson, Jeff D.
Ferreira, Elisabeth
Jilka, Robert L.
Zhou, Daohong
Almeida, Maria
O’Brien, Charles A.
author_facet Kim, Ha-Neui
Xiong, Jinhu
MacLeod, Ryan S.
Iyer, Srividhya
Fujiwara, Yuko
Cawley, Keisha M.
Han, Li
He, Yonghan
Thostenson, Jeff D.
Ferreira, Elisabeth
Jilka, Robert L.
Zhou, Daohong
Almeida, Maria
O’Brien, Charles A.
author_sort Kim, Ha-Neui
collection PubMed
description In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.
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spelling pubmed-75667012020-10-21 Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence Kim, Ha-Neui Xiong, Jinhu MacLeod, Ryan S. Iyer, Srividhya Fujiwara, Yuko Cawley, Keisha M. Han, Li He, Yonghan Thostenson, Jeff D. Ferreira, Elisabeth Jilka, Robert L. Zhou, Daohong Almeida, Maria O’Brien, Charles A. JCI Insight Research Article In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone. American Society for Clinical Investigation 2020-10-02 /pmc/articles/PMC7566701/ /pubmed/32870816 http://dx.doi.org/10.1172/jci.insight.138815 Text en © 2020 Kim et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Kim, Ha-Neui
Xiong, Jinhu
MacLeod, Ryan S.
Iyer, Srividhya
Fujiwara, Yuko
Cawley, Keisha M.
Han, Li
He, Yonghan
Thostenson, Jeff D.
Ferreira, Elisabeth
Jilka, Robert L.
Zhou, Daohong
Almeida, Maria
O’Brien, Charles A.
Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
title Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
title_full Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
title_fullStr Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
title_full_unstemmed Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
title_short Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence
title_sort osteocyte rankl is required for cortical bone loss with age and is induced by senescence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566701/
https://www.ncbi.nlm.nih.gov/pubmed/32870816
http://dx.doi.org/10.1172/jci.insight.138815
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