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Histone methyltransferase SETDB1 promotes osteogenic differentiation in osteoporosis by activating OTX2-mediated BMP-Smad and Wnt/β-catenin pathways

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Abstract

Osteogenic differentiation plays important roles in the pathogenesis of osteoporosis. In this study, we explored the regulatory mechanism of histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in osteoporosis. The common osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate osteoporosis-related genes using the PANTHER software, and the binding site between transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6 osteoporosis-related chromatin/chromatin binding protein or regulatory proteins (HDAC4, SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and osteoporosis tissues were collected from osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/β-catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/β-catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/β-catenin pathways in osteoporosis.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

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Funding

This study was supported by key natural and science projects of Bengbu Medical College (No. 2020byzd308).

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Authors and Affiliations

  1. Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China

    Lianying Hu & Bin Xu

  2. Department of Orthopedics, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, Anhui Province, People’s Republic of China

    Lianying Hu, Liangliang Luo, Ping Pan, Qiyu Jia & Ning Yang

  3. Clinical Laboratory, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, People’s Republic of China

    Zhen Cheng & Shujin Li

  4. Department of Anesthesiology and Perioperative Medicine, The Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, The Second Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China

    Lunan Wu

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Contributions

LH, ZC, LLL, and PP contributed to study design; SJL, QYJ, BX, and NY conducted study. LH, ZC, LLL, and LNW analyzed the data. PP drafted the manuscript. All the authors interpreted the data, revised the manuscript content, and approved the final version of manuscript. All the authors take responsibility for the integrity of the data analysis.

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Correspondence to Qiyu Jia, Ning Yang or Bin Xu.

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The current study was performed with the approval of the Ethics Committee of the Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University and performed in strict accordance with the Declaration of Helsinki (Protocol No.: HF2H-CE-2022–0317). Signed informed consents were obtained from all participants prior to enrollment and in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals (Protocol No.: HF2H-AE-2022–0317). Histone methyltransferase SETDB1 promotes osteogenic differentiation in osteoporosis by activating OTX2-mediated BMP-Smad and Wnt/β-catenin pathways.

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Hu, L., Cheng, Z., Wu, L. et al. Histone methyltransferase SETDB1 promotes osteogenic differentiation in osteoporosis by activating OTX2-mediated BMP-Smad and Wnt/β-catenin pathways. Human Cell 36, 1373–1388 (2023). https://doi.org/10.1007/s13577-023-00902-w

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