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CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice
The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870077/ https://www.ncbi.nlm.nih.gov/pubmed/36378535 http://dx.doi.org/10.1172/jci.insight.159107 |
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author | Yu, Degang Zhang, Shuhong Ma, Chao Huang, Sen Xu, Long Liang, Jun Li, Huiwu Fan, Qiming Liu, Guangwang Zhai, Zanjing |
author_facet | Yu, Degang Zhang, Shuhong Ma, Chao Huang, Sen Xu, Long Liang, Jun Li, Huiwu Fan, Qiming Liu, Guangwang Zhai, Zanjing |
author_sort | Yu, Degang |
collection | PubMed |
description | The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow and their roles in BMSCs’ differentiation. Antibody array revealed that CC chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSC differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypomethylation. Moreover, CCL3 inhibited BMSCs’ osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated Dickkopf-related protein 1 upregulation. Blocking CCL3 in vivo via neutralizing antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis and lays a foundation for the identification of new targets for senile osteoporosis treatment. |
format | Online Article Text |
id | pubmed-9870077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-98700772023-02-06 CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice Yu, Degang Zhang, Shuhong Ma, Chao Huang, Sen Xu, Long Liang, Jun Li, Huiwu Fan, Qiming Liu, Guangwang Zhai, Zanjing JCI Insight Research Article The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow and their roles in BMSCs’ differentiation. Antibody array revealed that CC chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSC differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypomethylation. Moreover, CCL3 inhibited BMSCs’ osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated Dickkopf-related protein 1 upregulation. Blocking CCL3 in vivo via neutralizing antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis and lays a foundation for the identification of new targets for senile osteoporosis treatment. American Society for Clinical Investigation 2023-01-10 /pmc/articles/PMC9870077/ /pubmed/36378535 http://dx.doi.org/10.1172/jci.insight.159107 Text en © 2023 Yu et al. https://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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Yu, Degang Zhang, Shuhong Ma, Chao Huang, Sen Xu, Long Liang, Jun Li, Huiwu Fan, Qiming Liu, Guangwang Zhai, Zanjing CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
title | CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
title_full | CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
title_fullStr | CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
title_full_unstemmed | CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
title_short | CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
title_sort | ccl3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870077/ https://www.ncbi.nlm.nih.gov/pubmed/36378535 http://dx.doi.org/10.1172/jci.insight.159107 |
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