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  1. Evaluation Summary:

    The paper by Sun et al. addresses the role of gasdermins GSDMD and GSDME in fracture healing and inflammation after injury. The study is very significant for the understanding the role of GSDMD and GSDME in bone homoeostasis and in particular fracture healing. The reported data are very strong and in support of the proposed/studied hypothesis.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Public Review:

    In the manuscript by Sun et al the authors examine the roles played by the gasdermin-interleukin axis in the fracture healing process. Gasdermins (GSDMs) form plasma membrane pores and thus enable secretion of interleukins 1β and 18. These proinflammatory interleukins then initiate fracture healing. The authors utilize a variety of models to demonstrate the importance of interleukin 1β in this process including: (1) GSDM knockout mice; (2) tibia fracture model and (3) interleukin 1 knockout mice. The use of various in vivo and in vitro testing is a strength of the manuscript convincingly demonstrating a role for interleukin 1β in fracture healing. A weakness of the manuscript is that a potential role for interleukin 18 is underdeveloped and not as convincing as that for interleukin 1β. The authors themselves point this out in the Discussion section. The authors raise the possibility that their findings are translationally relevant with the development of GSDM inhibitors for clinical use.

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