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Developmental growth plate cartilage formation suppressed by artificial light at night via inhibiting BMAL1-driven collagen hydroxylation

Cell Death & Differentiation volume 30, pages 1503–1516 (2023)Cite this article

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Abstract

Exposure to artificial light at night (LAN) can induce obesity, depressive disorder and osteoporosis, but the pernicious effects of excessive LAN exposure on tissue structure are poorly understood. Here, we demonstrated that artificial LAN can impair developmental growth plate cartilage extracellular matrix (ECM) formation and cause endoplasmic reticulum (ER) dilation, which in turn compromises bone formation. Excessive LAN exposure induces downregulation of the core circadian clock protein BMAL1, which leads to collagen accumulation in the ER. Further investigations suggest that BMAL1 is the direct transcriptional activator of prolyl 4-hydroxylase subunit alpha 1 (P4ha1) in chondrocytes, which orchestrates collagen prolyl hydroxylation and secretion. BMAL1 downregulation induced by LAN markedly inhibits proline hydroxylation and transport of collagen from ER to golgi, thereby inducing ER stress in chondrocytes. Restoration of BMAL1/P4HA1 signaling can effectively rescue the dysregulation of cartilage formation within the developmental growth plate induced by artificial LAN exposure. In summary, our investigations suggested that LAN is a significant risk factor in bone growth and development, and a proposed novel strategy targeting enhancement of BMAL1-mediated collagen hydroxylation could be a potential therapeutic approach to facilitate bone growth.

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Fig. 1: LAN inhibits growth plate cartilage ECM formation and causes ER dilation.
Fig. 2: Bmal1 knockout suppresses cartilage ECM formation and elicits ER dilation.
Fig. 3: BMAL1 deficiency inhibits collagen secretion and contributes to ER stress in vitro.
Fig. 4: Impaired COL2A1 hydroxylation in BMAL1 deficient chondrocytes triggers ER stress in a P4HA1-dependent manner.
Fig. 5: Transcriptional regulation by BMAL1 induces rhythmic expression of P4HA1 in chondrocytes.
Fig. 6: Restoration of BMAL1 expression reverses LAN-induced dysregulation of growth plate cartilage formation.
Fig. 7: Schematic illustration of the mechanism via which LAN inhibits cartilage ECM formation.

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Data availability

All data supporting the results are available from the corresponding author upon request.

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Acknowledgements

We would like to thank Prof. Anbing Shi (Huazhong University of Science and Technology) for constructive advice. We also thanks Prof. Ying Xu (Soochow University) for the Bmal1wt/− and Bmal1fl/fl mating pairs.

Funding

This research was funded by the National Natural Science Foundation of China for Key Program Projects (82030070, to LC) and General Program (82270950, to QT), Hubei Provincial Natural Science Fund for Creative Research Group (2020CFA014, to LC), Young Talent Program by Health Commission of Hubei Province (WJ2021Q059, to QT) and the Youth Clinical Research Fund of Chinese Stomatological Association (CSA-O2020-10, to QT).

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  1. These authors contributed equally: Guangjin Chen, Qingming Tang.

Authors and Affiliations

  1. Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Guangjin Chen, Qingming Tang, Shaoling Yu, Yufeng Shen, Jiwei Sun, Jinfeng Peng, Ying Yin, Guangxia Feng, Xiaofeng Lu, Gang Mei, Yifan Zhang & Lili Chen

  2. School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Guangjin Chen, Qingming Tang, Shaoling Yu, Yufeng Shen, Jiwei Sun, Jinfeng Peng, Ying Yin, Guangxia Feng, Xiaofeng Lu, Gang Mei, Yifan Zhang & Lili Chen

  3. Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China

    Guangjin Chen, Qingming Tang, Shaoling Yu, Yufeng Shen, Jiwei Sun, Jinfeng Peng, Ying Yin, Guangxia Feng, Xiaofeng Lu, Gang Mei, Yifan Zhang & Lili Chen

  4. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qian Wan

  5. Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China

    Luoying Zhang

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Contributions

GC, QT and LC performed the experiments, data analysis and drafted the manuscript. SY, JS and YS contributed to the materials and analysis methods. GF, GM, YZ, YY, JP and XL contributed to animal housing and animal experiments. QW and LZ supervised the mathematical aspects of this research. LC supervised the whole study and revised the manuscript.

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Correspondence to Lili Chen.

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All experiments were approved by the Institutional Animal Care and Use Committee of Tongji Medical College (LAUCU Number:2809).

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Chen, G., Tang, Q., Yu, S. et al. Developmental growth plate cartilage formation suppressed by artificial light at night via inhibiting BMAL1-driven collagen hydroxylation. Cell Death Differ 30, 1503–1516 (2023). https://doi.org/10.1038/s41418-023-01152-x

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