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MiR-601-induced BMSCs senescence accelerates steroid-induced osteonecrosis of the femoral head progression by targeting SIRT1

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Abstract

Background

The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is not only the primary pathological feature but also a major contributor to the pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH). Cellular senescence is one of the main causes of imbalanced BMSCs differentiation. The purpose of this study was to reveal whether cellular senescence could participate in the progression of SONFH and the related mechanisms.

Methods

The rat SONFH model was constructed, and rat BMSCs were extracted. Aging-related indicators were detected by SA-β-Gal staining, qRT-PCR and Western Blot experiments. Using H2O2 to construct a senescent cell model, and overexpressing and knocking down miR-601 and SIRT1 in hBMSCs, the effect on BMSCs differentiation was explored by qRT-PCR, Western Blot experiment, oil red O staining (ORO), alizarin red staining (ARS), and luciferase reporter gene experiment. A rat SONFH model was established to test the effects of miR-601 and metformin in vivo.

Results

The current study showed that glucocorticoids (GCs)-induced BMSCs senescence, which caused imbalanced osteogenesis and adipogenesis of BMSCs, was responsible for the SONFH progression. Further, elevated miR-601 caused by GCs was demonstrated to contribute to BMSCs senescence through targeting SIRT1. In addition, the anti-aging drug metformin was shown to be able to alleviate GCs-induced BMSCs senescence and SONFH progression.

Conclusions

Considering the role of BMSCs aging in the progression of SONFH, this provides a new idea for the prevention and treatment of SONFH.

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Availability of data and materials

The data that support the findings of this study are available from the Corresponding authors upon reasonable request.

Abbreviations

ALP:

Alkaline phosphatase

ARS:

Alizarin red staining

BMSCs:

Bone marrow mesenchymal stem cells

BV/TV:

Bone volume per tissue volume

C/EBPɑ:

CCAAT-enhancer-binding proteins ɑ

FABP4:

Fatty acid-binding protein 4

FNF:

Femoral neck fracture

GCs:

Glucocorticoids

H&E:

Hematoxylin and eosin staining

IHC:

Immunohistochemistry

LPS:

Lipopolysaccharide

MPS:

Methylprednisolone

OPN:

Osteopontin

ORO:

Oil red O staining

PPARγ:

Peroxisome proliferators-activated receptors γ

RUNX2:

Runt-related transcription factor 2

SIRT1:

Sirtuin1

SONFH:

Steroid-induced osteonecrosis of the femoral head

Tb.N:

Trabecular number

Tb.Sp:

Trabecular separation

Tb.Th:

Trabecular thickness

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Funding

The study was supported by the Natural Science Foundation of China (No. 32271179, 82102610); Chongqing Technology Innovation and Application Development Project (CQYC202010); the Natural Science Foundation of Chongqing Science and Technology Commission (No. cstc2020jcyj-msxmX0179); the Science Foundation for Top-notch Young Scholars of the First Affiliated Hospital of Chongqing Medical University (No. BJRC2021-02); the Science and Technology Research Project of Chongqing Sports Bureau (No. A202206, A202013, C202124); and the Science and Technology Research Project of Chongqing Education Commission (No. KJQN202200404). All the funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Author notes

  1. Boyu Tang and Yu Chen are co-first authors of the article.

Authors and Affiliations

  1. Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China

    Boyu Tang, Yu Chen, Pei Zhao, Wenlong Yan, Xiao Huang, Weiqian Jiang, Mingjie Sun, Hongrui Zhang, Dulei Xiang, Chengjie Lian & Jian Zhang

  2. Orthopedic Laboratory of Chongqing Medical University, Chongqing, China

    Boyu Tang, Yu Chen, Pei Zhao, Wenlong Yan, Xiao Huang, Weiqian Jiang, Mingjie Sun, Hongrui Zhang, Dulei Xiang, Chengjie Lian & Jian Zhang

  3. Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China

    Tingmei Chen

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Contributions

J.Z, C.L. and B.T. participated in the design of the study and carried out experiments. B.T., Y.C., M.S., H.Z., and D.X. conceived the experiments. B.T, P.Z, W.Y, X.H. and T.C. analyzed the data. B.T., C.L. and J.Z. wrote the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Correspondence to Chengjie Lian or Jian Zhang.

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(1) Title of the approved project: The role and molecular mechanism of miRNA-601 in steroid-induced necrosis of the femoral head; (2) Name of the institutional approval committee or unit: The First Affiliated Hospital of Chongqing Medical University and the Ethical Committee of Chongqing Medical University; (3) Approval number: 2022–005; (4) Date of approval: March 23, 2022.

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Tang, B., Chen, Y., Zhao, P. et al. MiR-601-induced BMSCs senescence accelerates steroid-induced osteonecrosis of the femoral head progression by targeting SIRT1. Cell. Mol. Life Sci. 80, 261 (2023). https://doi.org/10.1007/s00018-023-04903-8

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  • DOI: https://doi.org/10.1007/s00018-023-04903-8

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