Epigenetic mechanisms of Nsd1-mediated histone methylation modifications in chondrocyte ferroptosis in knee osteoarthritis

Authors

  • Rao Wang Bone and Joint Rehabilitation Department of TCM Orthopedic Center, Xi’an Honghui Hospital, Xi’an, China https://orcid.org/0009-0002-8159-1684
  • Da Shi Bone and Joint Rehabilitation Department of TCM Orthopedic Center, Xi’an Honghui Hospital, Xi’an, China
  • Xiaoni Pan Bone and Joint Rehabilitation Department of TCM Orthopedic Center, Xi’an Honghui Hospital, Xi’an, China
  • Anqi Ren Department of Clinical Pharmacy, Xi’an Honghui Hospital, Xi’an, China
  • Kai Jiang Department of Clinical Pharmacy, Xi’an Honghui Hospital, Xi’an, China

DOI:

https://doi.org/10.17305/bb.2024.10879

Keywords:

Knee osteoarthritis, ferroptosis, chondrocyte, Nsd1, SOX9, ACSL4

Abstract

Knee osteoarthritis (KOA) is a degenerative joint disease characterized by pain, stiffness, and impaired mobility, with current therapies offering limited efficacy. This study investigates the epigenetic role of nuclear receptor-binding SET domain protein 1 (NSD1) in KOA pathogenesis. A KOA mouse model was established, and adenoviral vectors were employed to upregulate Nsd1 and inhibit SRY-box transcription factor 9 (Sox9), followed by histopathological assessments. We examined changes in cell morphology, proliferation, viability, and ferroptosis-related markers. The expression of Nsd1, Sox9, and acyl-CoA synthetase long-chain family member 4 (Acsl4) was analyzed, along with the enrichment of Nsd1 and dimethylated lysine 36 of histone 3 (H3K36me2) on the Sox9 promoter and Sox9 on the Acsl4 promoter. Additionally, the binding relationship between Sox9 and the Acsl4 promoter sequence was analyzed. Our results revealed that Nsd1 expression was reduced in KOA mouse tissues and interleukin (IL)-1β-stimulated chondrocytes. Nsd1 upregulation alleviated KOA, promoted chondrocyte proliferation and viability, and inhibited ferroptosis. Mechanistically, Nsd1 enhanced H3K36me2 to upregulate Sox9 expression, which in turn suppressed Acsl4 expression and ferroptosis. Sox9 inhibition partially reversed the protective effect of Nsd1 overexpression. In summary, Nsd1 upregulation mitigates chondrocyte ferroptosis and ameliorates KOA by modulating H3K36me2 to upregulate Sox9 and downregulate Acsl4 expression.

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Epigenetic mechanisms of Nsd1-mediated histone methylation modifications in chondrocyte ferroptosis in knee osteoarthritis

Published

31-08-2024

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Research article

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How to Cite

1.
Epigenetic mechanisms of Nsd1-mediated histone methylation modifications in chondrocyte ferroptosis in knee osteoarthritis. Biomol Biomed [Internet]. 2024 Aug. 31 [cited 2024 Oct. 9];. Available from: https://bjbms.org/ojs/index.php/bjbms/article/view/10879