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

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 1

The alleviation of senile bone loss can be achieved by preventing the decline of BMAL1 induced by aging.

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The alleviation of senile bone loss can be achieved by preventing the de...
(A) Western blot analysis of the levels of BMAL1 in femurs of 1-, 2-, 4-week-old and 2-, 3-, 14-, 19-month-old mice, with quantitative data (n = 4). (B) Schematic diagram of the Bmal1-KO (Bmal1fl/fl) mouse model. (C) Schematic diagram of injection of the rAAV virus into knee joints. (D) Western blot analysis of BMAL1 protein levels in femurs and quantitative data. rAAV-ctrl or rAAV-Cre was injected into mice at 3 months of age, while rAAV-Cre was injected at 5 months of age (n = 3). (E) Representative images of micro-CT reconstruction of femurs corresponding to the samples in D, with quantitative data shown (n = 6). (F) Representative flow cytometry plot showing CD11–CD45–Sca1+CD29+ BMSCs corresponding to the samples in D. (G) Quantitative data for the flow cytometric results in F (n = 5). (H) Representative images of nonsenescent and senescent osteocyte in mice according to the TAF (white arrows) assay corresponding to the samples in D, with quantitative data (n = 4). (I) Western blot analysis of the BMAL1 protein levels in femurs of 4- and 15-month-old mice treated with solvent or NRS (3 mg/kg/d, oral administration) for 1 month, with quantitative data shown (n = 4). (J) Representative images of micro-CT reconstruction of femurs corresponding to the samples in I, with quantitative data (n = 6). (K) Representative flow cytometry plot showing CD11b–CD45–Sca1+CD29+ BMSCs corresponding to the samples in I. (L) The quantitative data for K (n = 6). (M) Representative images of nonsenescent and senescent osteocyte in mice according to the TAF (white arrows) assay corresponding to the samples in I, with quantitative data on the right (n = 4). Scale bars: 2 μm and 50 μm. *P < 0.05, **P < 0.01, and ***P < 0.001. Data in A, D, E, F, H, I, J, L, and M were analyzed by 1-way ANOVA with Tukey’s multiple-comparison test.