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Human-specific duplicate CHRFAM7A gene is associated with more severe osteoarthritis and amplifies pain behaviours
  1. Alice Courties1,2,
  2. Merissa Olmer1,
  3. Kevin Myers1,
  4. Phillip Ordoukhanian3,
  5. Steven R Head3,
  6. Padmaja Natarajan3,
  7. Francis Berenbaum2,
  8. Jérémie Sellam2,
  9. Martin K Lotz1
  1. 1Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
  2. 2INSERM UMRS 938, Hôpital Saint-Antoine, Service de rhumatologie, AP-HP, Sorbonne Université, Paris, France
  3. 3Center for Computational Biology & Bioinformatics and Genomics Core, Scripps Research, La Jolla, California, USA
  1. Correspondence to Professor Martin K Lotz, Department of Molecular Medicine, Scripps Research Institute Department of Molecular Medicine, Jupiter, Florida, USA; mlotz{at}scripps.edu

Abstract

Objectives CHRFAM7A is a uniquely human fusion gene that functions as a dominant negative regulator of alpha 7 acetylcholine nicotinic receptor (α7nAChR) in vitro. This study determined the impact of CHRFAM7A on α7nAChR agonist responses, osteoarthritis (OA) severity and pain behaviours and investigated mechanisms.

Methods Transgenic CHRFAM7A (TgCHRFAM7A) mice were used to determine the impact of CHRFAM7A on knee OA histology, pain severity in OA and other pain models, response to nAchR agonist and IL-1β. Mouse and human cells were used for mechanistic studies.

Results Transgenic (Tg) TgCHRFAM7A mice developed more severe structural damage and increased mechanical allodynia than wild type (WT) mice in the destabilisation of medial meniscus model of OA. This was associated with a decreased suppression of inflammation by α7nAchR agonist. TgCHRFAM7A mice displayed a higher basal sensitivity to pain stimuli and increased pain behaviour in the monoiodoacetate and formalin models. Dorsal root ganglia of TgCHRFAM7A mice showed increased macrophage infiltration and expression of the chemokine fractalkine and also had a compromised antinociceptive response to the α7nAchR agonist nicotine. Both native CHRNA7 and CHRFAM7A subunits were expressed in human joint tissues and the CHRFAM7A/CHRNA7 ratio was increased in OA cartilage. Human chondrocytes with two copies of CHRFAM7A had reduced anti-inflammatory responses to nicotine.

Conclusion CHRFAM7A is an aggravating factor for OA-associated inflammation and tissue damage and a novel genetic risk factor and therapeutic target for pain.

  • osteoarthritis
  • inflammation
  • chondrocytes

Data availability statement

No data are available.

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Data availability statement

No data are available.

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @larhumato

  • Contributors All authors contributed to the manuscript. Conceptualisation: AC, MKL, JS, FB; Methodology: AC, MO, KM, PO, SRH, PN, FB, JS, MKL; Acquisition of data : AC, MO, KM, PO, SRH, PN, FB, JS, MKL. Analysis of data: AC, MO, KM, PO, SRH, PN,FB, JS, MKL; Funding acquisition: AC, MKL; writing—original draft: AC, MKL; writing—review and editing: AC, MO, KM, PO, SRH, PN, FB, JS, MKL. MKL is the guarantor for this study.

  • Funding This work was supported by NIH grants AG049617 (Lotz) and AR079206 (Malfait). Alice Courties received a grant from the French Society of Rheumatology, the Assistance Publique - Hôpitaux de Paris and from Servier Institute.

  • 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.