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Purpose <p>Osteoarthritis (OA) pain can arise from inflammatory cytokines sensitizing neurons that innervate the temporomandibular joint (TMJ) and knee. <i>Clustered Regularly Interspaced Short Palindromic Repeats</i> (CRISPR)-based epigenome editing enables targeted repression of inflammatory receptors and offers a promising strategy to modify disease mechanisms. This study tested whether CRISPR epigenome editing of interleukin-1 receptor type 1 (IL1R1) in trigeminal ganglia (TG; TMJ-innervating) and dorsal root ganglia (DRG; knee-innervating) neurons could reduce OA-associated sensitization.</p> Methods <p>OA cartilage was collected from knee replacement patients and compared with healthy cadaveric cartilage. Rat TG and DRG neurons were cultured with IL-1β on tissue culture plastic or cartilage explants, loaded with calcium dye, and subjected to thermal stimulation. Neurons were transduced with lentiviral CRISPR-dCas9-KRAB vectors targeting IL1R1 or with nontargeting controls, and heat-evoked calcium transients were measured.</p> Results <p>Exposure to IL-1β and OA cartilage both increased the proportion of TG and DRG neurons exhibiting heat-induced calcium transients compared with controls. CRISPR epigenome editing of IL1R1 abolished sensitization in DRG neurons, restoring responses to healthy cartilage levels. In TG neurons, editing reduced maximum calcium responses to baseline but did not fully normalize the percentage of sensitized cells, suggesting additional OA factors contribute to TMJ pain.</p> Conclusion <p>CRISPR epigenome editing of IL1R1 in joint-innervating neurons reduces OA cartilage-induced sensitization. These results highlight differential mechanisms underlying OA cartilage driven DRG and TG neuron sensitization and establish epigenome editing as a potential therapeutic strategy to target OA-associated sensitization in the knee and TMJ.</p>

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CRISPR Epigenome Editing of IL1R1 Expression of Neurons that Innervate the Temporomandibular Joint or Knee Causes Reduced Sensitization to Osteoarthritic Environment

  • 期刊论文

  • 发表日期：

    2026年4月8日

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  • Joshua D. Stover,
  • Robby D. Bowles,
  • Yenisel Cruz-Almeida,
  • Robert M. Caudle,
  • Kyle D. Allen,
  • Armen Akopian,
  • Benjamin Arenkiel,
  • Basak Ayaz,
  • Yangjin Bae,
  • Bruna Balbino de Paula,
  • Anita Bandrowski,
  • Mario Danilo Boada,
  • Jacqueline Boccanfuso,
  • Jyl Boline,
  • Dawen Cai,
  • Carpio,
  • Dellina Lane,
  • Robert Caudle,
  • Racel Cela,
  • Yong Chen,
  • Rui Chen,
  • Brian Constantinescu,
  • Cortez,
  • Ibdanelo,
  • M Franklin Dolwick,
  • Chris Donnelly,
  • Zelong Dou,
  • Joshua Emrick,
  • Malin Ernberg,
  • Danielle Freburg-Hoffmeister,
  • Spencer Fullam,
  • Janak Gaire,
  • Akash Gandhi,
  • Benjamin Goolsby,
  • Stacey Greene,
  • Nele Haelterman,
  • Michael Iadarola,
  • Shingo Ishihara,
  • Azeez Ishola,
  • Sudhish Jayachandran,
  • Zixue Jin,
  • Frank Ko,
  • Priya Kulkarni,
  • Zhao Lai,
  • Brendan Lee,
  • Yona Levites,
  • Carolina Leynes,
  • Jun Li,
  • Martin Lotz,
  • Lindsey Macpherson,
  • Tristan Maerz,
  • Camilla Majano,
  • Anne Marie Malfait,
  • Maryann Martone,
  • Bella Mehta,
  • Richard Miller,
  • Rachel Miller,
  • Michael Newton,
  • Alia Obeidat,
  • Merissa Olmer,
  • Dana Orange,
  • Miguel Otero,
  • Kevin Otto,
  • Folly Patterson,
  • Marlena Pela,
  • Sienna Perry,
  • Theodore Price,
  • Hernan Prieto,
  • Russell Ray,
  • Dongjun Ren,
  • Margarete Ribeiro Dasilva,
  • Alexus Roberts,
  • Juliane Rolim deLavor,
  • Elizabeth Ronan,
  • Oscar Ruiz,
  • Shad Smith,
  • Mairobys Socorro,
  • Kaitlin Southern,
  • Joshua Stover,
  • Michael Strinden,
  • Hannah Swahn,
  • Evelyne Tantry,
  • Sue Tappan,
  • Luis Tovias Sanchez,
  • Airam Vivanco-Estela,
  • Joost Wagenaar,
  • Lai Wang,
  • Kim Worley,
  • Joshua Wythe,
  • Jiansen Yan,
  • Julia Younis,
  • Alejandro J. Almarza

摘要

Purpose

Osteoarthritis (OA) pain can arise from inflammatory cytokines sensitizing neurons that innervate the temporomandibular joint (TMJ) and knee. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenome editing enables targeted repression of inflammatory receptors and offers a promising strategy to modify disease mechanisms. This study tested whether CRISPR epigenome editing of interleukin-1 receptor type 1 (IL1R1) in trigeminal ganglia (TG; TMJ-innervating) and dorsal root ganglia (DRG; knee-innervating) neurons could reduce OA-associated sensitization.

Methods

OA cartilage was collected from knee replacement patients and compared with healthy cadaveric cartilage. Rat TG and DRG neurons were cultured with IL-1β on tissue culture plastic or cartilage explants, loaded with calcium dye, and subjected to thermal stimulation. Neurons were transduced with lentiviral CRISPR-dCas9-KRAB vectors targeting IL1R1 or with nontargeting controls, and heat-evoked calcium transients were measured.

Results

Exposure to IL-1β and OA cartilage both increased the proportion of TG and DRG neurons exhibiting heat-induced calcium transients compared with controls. CRISPR epigenome editing of IL1R1 abolished sensitization in DRG neurons, restoring responses to healthy cartilage levels. In TG neurons, editing reduced maximum calcium responses to baseline but did not fully normalize the percentage of sensitized cells, suggesting additional OA factors contribute to TMJ pain.

Conclusion

CRISPR epigenome editing of IL1R1 in joint-innervating neurons reduces OA cartilage-induced sensitization. These results highlight differential mechanisms underlying OA cartilage driven DRG and TG neuron sensitization and establish epigenome editing as a potential therapeutic strategy to target OA-associated sensitization in the knee and TMJ.