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H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and cartilage homeostasis

Cell Death & Differentiation volume 31, pages 106–118 (2024)Cite this article

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Abstract

Osteoarthritis (OA) is one of the most common joint diseases, there are no effective disease-modifying drugs, and the pathological mechanisms of OA need further investigation. Here, we show that H3K36 methylations were decreased in senescent chondrocytes and age-related osteoarthritic cartilage. Prrx1-Cre inducible H3.3K36M transgenic mice showed articular cartilage destruction and osteophyte formation. Conditional knockout Nsd1Prrx1-Cre mice, but not Nsd2Prrx1-Cre or Setd2Prrx1-Cre mice, replicated the phenotype of K36M/+; Prrx1-Cre mice. Immunostaining results showed decreased anabolic and increased catabolic activities in Nsd1Prrx1-Cre mice, along with decreased chondrogenic differentiation. Transcriptome and ChIP-seq data revealed that Osr2 was a key factor affected by Nsd1. Intra-articular delivery of Osr2 adenovirus effectively improved the homeostasis of articular cartilage in Nsd1Prrx1-Cre mice. In human osteoarthritic cartilages, both mRNA and protein levels of NSD1 and OSR2 were decreased. Our results indicate that NSD1-induced H3K36 methylations and OSR2 expression play important roles in articular cartilage homeostasis and OA. Targeting H3K36 methylation and OSR2 would be a novel strategy for OA treatment.

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Fig. 1: H3K36 methylations decreased in aged cells and articular cartilage.
Fig. 2: Mice with K36M transgenic or Nsd1 knockout developed osteoarthritis.
Fig. 3: Nsd1 deficiency disrupted articular cartilage homeostasis.
Fig. 4: Disturbed cell proliferation, differentiation and metabolism after NSD1 knockout.
Fig. 5: Osr2 was regulated by NSD1 through H3K36 methylation.
Fig. 6: Osr2 complement could rescue the defect in chondrogenic differentiation and cartilage homeostasis caused by Nsd1 knockout.
Fig. 7: NSD1 and OSR2 were decreased in osteoarthritic cartilage.

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Data availability

All data generated or analyzed during this study are included in this published article (and its Supplementary information files). The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Xinyuan Liu (Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai) for providing vectors and reagents related to the adenovirus package. We also thank the members of the Zou lab for helpful discussions.

Funding

This work was supported by the National Key Research and Development Program of China (2022YFA1106800, 2022YFA0806600), the National Natural Science Foundation of China (NSFC) (82230082, 81991512, 82202742, 81902212), the Strategic Priority Research Program of the Chinese Academy of Science (XDB0570000), the CAS Project for Young Scientists in Basic Research (YSBR-077), the Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1- 9000- 22- 4002).

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  1. These authors contributed equally: Rui Shao, Jinlong Suo, Zhong Zhang.

Authors and Affiliations

  1. Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Rui Shao, Jinlong Suo, Yiyang Ma, Mengxue Liu, Changqing Zhang & Weiguo Zou

  2. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, 200031, China

    Zhong Zhang, Yang Wen & Weiguo Zou

  3. Department of Orthopedics, Rehabilitation center, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, 310014, China

    Mingxiang Kong & Qing Bi

  4. Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892, USA

    Lenan Zhuang & Kai Ge

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Contributions

WZ and RS designed the research; RS, JS, ZZ performed the research; LZ, KG, CZ and QB contributed reagents and analytical tools; MK and QB collected human cartilage samples; RS, JS, ZZ and WZ analyzed the data; RS and WZ wrote the paper.

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Correspondence to Changqing Zhang or Weiguo Zou.

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The authors declare no competing interests.

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The experimental protocol for animal studies was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the CAS Center for Excellence in Molecular Cell Sciences, Chinese Academy of Sciences. Human articular cartilage samples were obtained with the informed consent of the patients and the approval of the ethics committee of Shanghai Sixth People’s Hospital and Zhejiang Provincial People’s Hospital.

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Shao, R., Suo, J., Zhang, Z. et al. H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and cartilage homeostasis. Cell Death Differ 31, 106–118 (2024). https://doi.org/10.1038/s41418-023-01244-8

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