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Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus
  1. Hannah Swahn1,
  2. Kun Li1,
  3. Tomas Duffy1,
  4. Merissa Olmer1,
  5. Darryl D D'Lima1,2,
  6. Tony S Mondala3,
  7. Padmaja Natarajan3,
  8. Steven R Head3,
  9. Martin K Lotz1
  1. 1Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
  2. 2Shiley Center for Orthopaedic Research and Education at Scripps Clinic, Scripps Health, La Jolla, California, USA
  3. 3Center for Computational Biology & Bioinformatics and Genomics Core, Scripps Research, La Jola, California, USA
  1. Correspondence to Professor Martin K Lotz, Department of Molecular Medicine, Scripps Research, La Jolla, CA 92037, USA; mlotz{at}scripps.edu

Abstract

Objectives Single-cell level analysis of articular cartilage and meniscus tissues from human healthy and osteoarthritis (OA) knees.

Methods Single-cell RNA sequencing (scRNA-seq) analyses were performed on articular cartilage and meniscus tissues from healthy (n=6, n=7) and OA (n=6, n=6) knees. Expression of genes of interest was validated using immunohistochemistry and RNA-seq and function was analysed by gene overexpression and depletion.

Results scRNA-seq analyses of human knee articular cartilage (70 972 cells) and meniscus (78 017 cells) identified a pathogenic subset that is shared between both tissues. This cell population is expanded in OA and has strong OA and senescence gene signatures. Further, this subset has critical roles in extracellular matrix (ECM) and tenascin signalling and is the dominant sender of signals to all other cartilage and meniscus clusters and a receiver of TGFβ signalling. Fibroblast activating protein (FAP) is also a dysregulated gene in this cluster and promotes ECM degradation. Regulons that are controlled by transcription factor ZEB1 are shared between the pathogenic subset in articular cartilage and meniscus. In meniscus and cartilage cells, FAP and ZEB1 promote expression of genes that contribute to OA pathogenesis, including senescence.

Conclusions These single-cell studies identified a senescent pathogenic cell cluster that is present in cartilage and meniscus and has FAP and ZEB1 as main regulators which are novel and promising therapeutic targets for OA-associated pathways in both tissues.

  • osteoarthritis
  • chondrocytes
  • arthritis

Data availability statement

Data will be available in GEO.

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Data availability statement

Data will be available in GEO.

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors MKL, TD and DD'L. designed the study. HS, TD, MO, TM and KL performed the experiments. HS and PN analysed the data. SRH and TSM provided methodology. MKL supervised the project. HS and MKL drafted the paper, which was approved by all coauthors. MKL acts as guarantor.

  • Funding National Institutes of Health grant R01AG049617.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.