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TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis

Cell Death & Differentiation (2022)Cite this article

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A Correction to this article was published on 21 February 2022

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Abstract

Dysfunction of mRNA or RNA-binding proteins (RBPs) causes cellular aging and age-related degenerative diseases; however, information regarding the mechanism through which RBP-mediated posttranscriptional regulation affects cellular aging and related disease processes is limited. In this study, PUM1 was found to be associated with the self-renewal capacity and aging process of human mesenchymal stem cells (MSC). PUM1 interacted with the 3’-untranslated region of Toll-like receptor 4 (TLR4) to suppress TLR4 mRNA translation and regulate the activity of nuclear factor-κB (NF-κB), a master regulator of the aging process in MSCs. PUM1 overexpression protected MSCs against H2O2-induced cellular senescence by suppressing TLR4-mediated NF-κB activity. TLR4-mediated NF-κB activation is a key regulator in osteoarthritis (OA) pathogenesis. PUM1 overexpression enhanced the chondrogenic potential of MSCs even under the influence of inflammation-inducing factors, such as lipopolysaccharide (LPS) or interleukin-1β (IL-1β), whereas the chondrogenic potential was reduced following the PUM1 knockdown-mediated TLR4 activation. PUM1 levels decreased under inflammatory conditions in vitro and during OA progression in human and mouse disease models. PUM1 knockdown in human chondrocytes promoted chondrogenic phenotype loss, whereas PUM1 overexpression protected the cells from inflammation-mediated disruption of the chondrogenic phenotype. Gene therapy using a lentiviral vector encoding mouse PUM1 showed promise in preserving articular cartilage integrity in OA mouse models. In conclusion, PUM1 is a novel suppressor of MSC aging, and the PUM1-TLR4 regulatory axis represents a potential therapeutic target for OA.

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Fig. 1: KD of PUM1 induces cellular senescence in mesenchymal stem cells.
Fig. 2: PUM1 interacts with the TLR4 mRNA and downregulates NF-κB activity in MSCs.
Fig. 3: PUM1 overexpression alleviates H2O2-induced cellular senescence.
Fig. 4: PUM1 overexpression preserves the high chondrogenic potential of MSCs in an inflammatory environment.
Fig. 5: PUM1 and TLR4 are inversely detected in the inflammatory environment in vitro and human OA cartilage tissues.
Fig. 6: PUM1 protects chondrocytes from inflammation, and NORAD may be an upstream regulator of the PUM1-TLR4 axis.
Fig. 7: Gene therapy with a lentiviral vector encoding PUM1 in a mouse model for OA.

Data availability

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

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Funding

This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2019R1I1A1A01060928, NRF-2018K1A4A3A01064257, NRF-2018R1A2B3003446, and NRF-2021R1A5A2022318).

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 03722, South Korea

    Dong Suk Yoon, Kyoung-Mi Lee, Yoorim Choi, Eun Ae Ko, Sehee Cho, Kwang Hwan Park & Jin Woo Lee

  2. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea

    Kyoung-Mi Lee & Jin Woo Lee

  3. Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, South Korea

    Na-Hyun Lee, Jung-Hwan Lee & Hae-Won Kim

  4. Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, South Korea

    Na-Hyun Lee, Jung-Hwan Lee & Hae-Won Kim

  5. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South Korea

    Sehee Cho & Jin Woo Lee

  6. Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, 31116, South Korea

    Jung-Hwan Lee & Hae-Won Kim

  7. UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, South Korea

    Jung-Hwan Lee & Hae-Won Kim

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  1. Dong Suk Yoon
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Contributions

DSY. designed the study, performed the experiments, analyzed the data, and wrote the paper. K-ML, YC, EAK, N-HL, SC, KHP, and J-HL performed in vitro and in vivo experiments. H-WK and JWL designed the study, interpreted the data, and revised the paper.

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Correspondence to Hae-Won Kim or Jin Woo Lee.

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Animal handling and procedures were approved and conducted as per the approval of the Institutional Animal Care and Use Committee (IACUC) protocol of the Yonsei University College of Medicine (Approval number: IACUC-2016-0099).

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Yoon, D.S., Lee, KM., Choi, Y. et al. TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis. Cell Death Differ (2022). https://doi.org/10.1038/s41418-021-00925-6

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