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Endothelial BMAL1 decline during aging leads to bone loss by destabilizing extracellular fibrillin-1
Ying Yin, … , Luoying Zhang, Lili Chen
Ying Yin, … , Luoying Zhang, Lili Chen
Published December 16, 2024
Citation Information: J Clin Invest. 2024;134(24):e176660. https://doi.org/10.1172/JCI176660.
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Research Article Aging Bone biology Article has an altmetric score of 2

Endothelial BMAL1 decline during aging leads to bone loss by destabilizing extracellular fibrillin-1

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Abstract

The occurrence of aging is intricately associated with alterations in circadian rhythms that coincide with stem cell exhaustion. Nonetheless, the extent to which the circadian system governs skeletal aging remains inadequately understood. Here, we noticed that skeletal aging in male mice was accompanied by a decline in a core circadian protein, BMAL1, especially in bone marrow endothelial cells (ECs). Using male mice with endothelial KO of aryl hydrocarbon receptor nuclear translocator–like protein 1 (Bmal1), we ascertained that endothelial BMAL1 in bone played a crucial role in ensuring the stability of an extracellular structural component, fibrillin-1 (FBN1), through regulation of the equilibrium between the extracellular matrix (ECM) proteases thrombospondin type 1 domain–containing protein 4 (THSD4) and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which promote FBN1 assembly and breakdown, respectively. The decline of endothelial BMAL1 during aging prompted excessive breakdown of FBN1, leading to persistent activation of TGF-β/SMAD3 signaling and exhaustion of bone marrow mesenchymal stem cells. Meanwhile, the free TGF-β could promote osteoclast formation. Further analysis revealed that activation of ADAMTS4 in ECs lacking BMAL1 was stimulated by TGF-β/SMAD3 signaling through an ECM-positive feedback mechanism, whereas THSD4 was under direct transcriptional control by endothelial BMAL1. Our investigation has elucidated the etiology of bone aging in male mice by defining the role of ECs in upholding the equilibrium within the ECM, consequently coordinating osteogenic and osteoclastic activities and retarding skeletal aging.

Authors

Ying Yin, Qingming Tang, Jingxi Yang, Shiqi Gui, Yifan Zhang, Yufeng Shen, Xin Zhou, Shaoling Yu, Guangjin Chen, Jiwei Sun, Zhenshuo Han, Luoying Zhang, Lili Chen

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Figure 5

An imbalance in THSD4/ADAMTS4 signaling results in the degradation of the extracellular structural component FBN1.

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An imbalance in THSD4/ADAMTS4 signaling results in the degradation of th...
(A) Immunofluorescence of FBN1 and F-actin in femurs corresponding to the samples in Figure 4I (n = 3). Scale bars: 20 μm and 5 μm (enlarged insets). (B) Immunogold labeling of FBN1 in femurs corresponding to the samples in Figure 4I. Red arrowheads indicate FBN1 fibers. Scale bars: 1 μm and 200 nm (enlarged insets). (C) Quantitative data for the images in B (n = 4). (D) Schematic diagram of animal experiments in Bmal1 fl/fl mice injected with rAAV-Cdh5-Cre, and rAAV-Thsd4 or rADAMTS4. (E) Immunofluorescence images of FBN1 and F-actin in femurs corresponding to the samples in D (n = 3). Scale bars: 20 μm and 5 μm (enlarged insets). (F) Immunogold labeling of FBN1 in femurs corresponding to the samples in D, with quantitative data shown (n = 4). Red arrowheads indicate FBN1 fibers. *P < 0.05 and ***P < 0.001. Data in C and F were analyzed by 1-way ANOVA with Tukey’s multiple-comparison test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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