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CircZNF367 suppresses osteogenic differentiation of human bone marrow mesenchymal stromal/stem cells via reducing HuR-mediated mRNA stability of LRP5

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Abstract

Osteoporosis is a highly prevalent disease characterized by bone mass loss and structural deterioration. There are evidences that altered differentiation of human bone marrow mesenchymal stromal/stem cells (hBMSCs) is a major cause for osteoporosis. Recent studies suggest that circular RNAs (circRNAs) are dysregulated in osteoporosis patients and involved in the pathogenesis of osteoporosis. In the present study, we are aimed to analyze the circRNA expression profiles in osteoporosis patients and identify potential circRNAs that involved in the differentiation of hBMSCs during osteoporosis. Transcriptome RNA-sequencing was conducted to search for differentially expressed circRNAs. Transwell assay, ARS and ALP staining, and ectopic bone formation model were performed to evaluate osteogenic differentiation of hBMSCs. RNA pull-down assay, RNA immunoprecipitation, western blot, and in vitro binding assay were conducted to evaluate the interaction of circRNAs and RNA-binding protein HuR. We found that hsa_circ_0008842 (designated as circZNF367) was upregulated in osteoporosis patients and decreased in hBMSCs during osteogenic differentiation. CircZNF367 overexpression suppressed migration, invasion and osteogenic differentiation of hBMSCs in vitro and in vivo. In comparison, knockdown of circZNF367 promoted migration, invasion and osteogenic differentiation of hBMSCs. CircZNF367 could interact with the RNA-binding protein HuR, thus reduced the mRNA stability of LRP5. Furthermore, HuR overexpression or LRP5 restoration abrogated the effects of circZNF367 overexpression on osteogenic differentiation of hBMSCs. Our results indicated that circZNF367 played a role in osteogenic differentiation of hBMSCs via reducing HuR-mediated mRNA stability of LRP5.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China

    Gengyan Liu, Zhengguang Wang & Yong Zhou

  2. Changsha Blood Center, Changsha, 410013, Hunan, China

    Jia Luo

  3. Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China

    Yong Li

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All authors guaranteed the integrity of the entire study. The experiments were conducted by Gengyan Liu, Jia Luo and Zhengguang Wang. Clinical studies were conducted by Yong Li, Gengyan Liu and Jia Luo. Data was analyzed by Zhou Yong. Manuscript was prepared and reviewed by Yong Li. All authors have read and approved the manuscript.

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The protocol of our study for human were followed with the ethicaal standards of the institutional committee of The Third Xiangya Hospital (Approve no. 2017-R17021) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The use of animals in our study was approved and we strictly followed the ethical standards of the ethics committee of The Third Xiangya Hospital.

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13577_2022_798_MOESM1_ESM.jpg

Supplementary file1 (JPG 1352 KB) Supplementary Figure 1. The effect of circZNF367 overexpression on proliferation, colony formation, apoptosis and bone formation of BMSCs. A, hBMSCs were transduced with circZNF367 expression lentivirus or EV control, then relative cell viability at indicated times was evaluated by CCK-8 assay. B–C, hBMSCs (4000/well) transduced with circZNF367 expression lentivirus or EV control were used for colony formation assay (B). Number of colony number per well was shown (C). D–E, hBMSCs were transduced with circZNF367 expression lentivirus or EV control, then stained with Annexin-V FITC and PI for flow cytometry analysis (D). The percentage of Annexin-V apoptotic cells was shown (E). All assays were done in triplicates. *P＜ 0.05

13577_2022_798_MOESM2_ESM.jpg

Supplementary file2 (JPG 664 KB) Supplementary Figure 2. The influence of circZNF367 overexpression on adipogenic differentiation markers of BMSCs. hBMSCs transduced with circZNF367 expression lentivirus or EV control were cultured with adipogenic-inducing medium for 14 days, then relative CEBPα and PPARγ expression were evaluated by qRT-PCR (H) and western blot (I). n.s. = not significant

13577_2022_798_MOESM3_ESM.jpg

Supplementary file3 (JPG 1573 KB) Supplementary Figure 3. The effect of circZNF367 knockdown on proliferation, colony formation, apoptosis and bone formation of BMSCs. A, hBMSCs were transduced with sh-circ-1, sh-circ-2 or sh-NC lentivirus vector, then relative cell viability at indicated times was evaluated by CCK-8 assay. B–C, hBMSCs (4000/well) transduced with sh-circ-1, sh-circ-2 or sh-NC lentivirus vector were used for colony formation assay (B). Number of colony number per well was shown (C). D–E, hBMSCs were transduced with sh-circ-1, sh-circ-2 or sh-NC lentivirus vector, then stained with Annexin-V FITC and PI for flow cytometry analysis (D). The percentage of Annexin-V apoptotic cells was shown (E). All assays were done in triplicates. *P＜ 0.05

13577_2022_798_MOESM4_ESM.jpg

Supplementary file4 (JPG 1352 KB) Supplementary Figure S4. The influence of cricZNF367 on the downstream targets of Wnt/β-catenin signaling. A–B, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of hBMSCs transduced with circZNF367 expression lentivirus or EV control. C, hBMSCs were transduced with circZNF367 expression lentivirus or EV control, then relative LRP5 expression was evaluated by qRT-PCR. D–E, hBMSCs were transduced with circZNF367, EV, sh-circ-1, sh-circ-2 or sh-NC vector, then relative expression of indicated genes were evaluated by qRT-PCR. All assays were done in triplicates. *P＜ 0.05

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Liu, G., Luo, J., Wang, Z. et al. CircZNF367 suppresses osteogenic differentiation of human bone marrow mesenchymal stromal/stem cells via reducing HuR-mediated mRNA stability of LRP5. Human Cell 36, 146–162 (2023). https://doi.org/10.1007/s13577-022-00798-y

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