Genetic regulation of injury-induced heterotopic ossification in adult zebrafish

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 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 in response to micro-fractures in combination with muscle injury. These findings indicate that clinically-emulated injuries in zebrafish can lead to osteo-induction and proliferation as observed in heterotopic ossification in myositis ossificans traumatica. Exploiting this model, we analysed the penetrance and expressivity of heterotopic ossification and defined the transcriptional response to trauma, identifying differentially regulated genes. Taking advantage of defined mutants in several of these candidates, we explored their impact on heterotopic bone formation. Our findings revealed that an increase in potassium channel Kcnk5b activity potentiates injury response. In contrast, we demonstrate that inflammatory responses are essential for the ectopic bone growth, as mutations in Interleukin 11 receptor paralogue (Il11ra) exhibit a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signaling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.

• Publication year

  2024

• Venue

  bioRxiv

• Publication date

  2024-02-12

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2024.02.09.579618PMID 38736327PMCID 11152560
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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