Genetic regulation of injury-induced heterotopic ossification in adult zebrafish

Arun-Kumar Kaliya-Perumal, Cenk Celik , Tom J. Carney, Matthew P. Harris, Philip Ingham

Research output: Contribution to journalArticlepeer-review

Abstract

Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically emulating injuries, as observed in human myositis ossificans traumatica. Using this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in the activity of the potassium channel Kcnk5b potentiates injury response, whereas loss of function of the interleukin 11 receptor paralogue (Il11ra) resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.
Original languageEnglish
Article numberdmm050724
JournalDisease Models and Mechanisms
Volume17
Issue number5
Early online date31 May 2024
DOIs
Publication statusPublished - 31 May 2024

Data Availability Statement

The FASTQ files of the raw RNA-sequencing data are openly available at the NTU
research data repository [DR-NTU (Data)] at https://doi.org/10.21979/N9/HEJN6X.

Acknowledgements

We sincerely thank Dr Sven Reischauer for generously providing the il11ra−/− mutant zebrafish. We also thank the McMenamin laboratory for assistance with performing the micro-CT scans. We extend our gratitude to all the staff at LKCMedicine Research Administration and Support Services (RASS), with special acknowledgment to the Health and Safety Committee members and the Animal Research Facility (ARF) staff. We are indebted to Azmi Bin Ja'afar, Joshua Gan Lan Teng and Neo Sui Hoon for maintenance of our zebrafish lines.

Keywords

  • Contusion
  • Heterotopic ossification
  • Interleukin 11
  • Myositis ossificans
  • Potassium channels

ASJC Scopus subject areas

  • Immunology and Microbiology (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)

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