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H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and

Rui Shao1, Jinlong Suo1, Zhong Zhang2

  • 1Institute 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.

Cell Death and Differentiation
|November 27, 2023
PubMed

Insights

Reduced H3K36 methylation and NSD1 expression contribute to osteoarthritis (OA). Restoring these factors, particularly through OSR2, may offer novel therapeutic strategies for this common joint disease.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Orthopedics

Background:

  • Osteoarthritis (OA) is a prevalent joint disease with limited disease-modifying treatments.
  • Pathological mechanisms underlying OA require further elucidation.
  • H3K36 methylation is implicated in cellular senescence and age-related cartilage degeneration.

Purpose of the Study:

  • To investigate the role of H3K36 methylation and associated enzymes in osteoarthritis pathogenesis.
  • To identify key molecular pathways regulated by H3K36 methylation in chondrocytes.
  • To explore potential therapeutic targets for osteoarthritis based on these findings.

Main Methods:

  • Generation and analysis of transgenic mouse models (H3.3K36M, Nsd1Prrx1-Cre, Nsd2Prrx1-Cre, Setd2Prrx1-Cre).
  • Histological examination of articular cartilage for destruction and osteophyte formation.
  • Immunostaining for anabolic/catabolic markers and chondrogenic differentiation.
  • Transcriptome and Chromatin Immunoprecipitation sequencing (ChIP-seq) to identify target genes.
  • Adenovirus-mediated delivery of Osr2 for therapeutic intervention.

Main Results:

  • Decreased H3K36 methylation observed in senescent chondrocytes and osteoarthritic cartilage.
  • Nsd1 knockout mice (Nsd1Prrx1-Cre) exhibited OA phenotypes, including cartilage destruction and altered cellular activity.
  • Osr2 identified as a key downstream target of Nsd1, crucial for articular cartilage homeostasis.
  • Intra-articular Osr2 delivery ameliorated OA symptoms in Nsd1-deficient mice.
  • Reduced NSD1 and OSR2 expression confirmed in human osteoarthritic cartilage samples.

Conclusions:

  • NSD1-mediated H3K36 methylation and subsequent OSR2 expression are critical for maintaining articular cartilage health.
  • Dysregulation of this pathway contributes significantly to osteoarthritis development.
  • Targeting H3K36 methylation and OSR2 represents a promising novel therapeutic strategy for osteoarthritis.

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