Contusions that reshape bone produce tidy conclusions

After an injury to muscle and connective tissue, the damaged area is normally replaced with new soft tissues. However, after repeated or egregious contusions, erroneous repair can lead to growth of bone spurs and bone nodules that jut into soft tissue (heterotopic ossifications). Key mysteries remain about this condition, known as myositis ossificans traumatica (MOT). How does genetic background influence this acquired condition? How can the effects be mitigated? To answer questions like these, prior work has generated several heterotopic ossification models, but they each have limitations. An ideal system should swiftly and consistently cause excess bone growth within a wild-type animal that is also suited to rapid genetic study.In this issue, Arun-Kumar Kaliya-Perumal, Matthew Harris, Philip Ingham and colleagues present a simple injury paradigm that produces consistent heterotopic ossifications in the dorsal thoracic region or pectoral fin of wild-type zebrafish. After an initial wound, the injury sites were prodded twice at 48-hour intervals to disrupt the normal course of healing. Within a month, bony spurs were seen at the fin rays or intermuscular bones, depending on the injury site. In this study, heterotopic ossification at the pectoral fin arose with 100% penetrance, making this injury site particularly tractable for experiments. Because this is a zebrafish model, many established transgenic tools are available for cell labeling and live imaging. The injuries can also be performed in mutant or overexpression lines, allowing functional tests of the underpinning mechanisms. Here, the authors identified two pathways upregulated during MOT, which modify the severity of heterotopic ossification. They suggest that normal function of the potassium channel subfamily K member 5 (Kcnk5b) impedes bony overgrowth, whereas the inflammatory gene il11ra worsens MOT severity in the pectoral fin. Both genes (kcnk5b and il11ra) provide a glimpse at the processes that control MOT.This study shows that the onset and progression of heterotopic ossification is not left to chance. In zebrafish, MOT-like phenotypes can be induced reliably, seen clearly and modified genetically. These findings provide lessons that should help us understand MOT in humans and, perhaps, provide insights into normal regeneration as well. MOT is an acquired condition, so it may arise through cellular processes present in all of us but, in the disease setting, these processes may have simply been tilted out of balance. I am excited to see what further insights into development, regeneration and aberrant bone growth will come from this new injury paradigm.