TY - JOUR TI - Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling AU - Sun, Kai AU - Wang, Chun AU - Xiao, Jianqiu AU - Brodt, Michael D AU - Yuan, Luorongxin AU - Yang, Tong AU - Alippe, Yael AU - Hu, Huimin AU - Hao, Dingjun AU - Abu-Amer, Yousef AU - Silva, Matthew J AU - Shen, Jie AU - Mbalaviele, Gabriel A2 - Safadi, Fayez A2 - Zaidi, Mone A2 - Isales, Carlos VL - 11 PY - 2022 DA - 2022/03/04 SP - e75753 C1 - eLife 2022;11:e75753 DO - 10.7554/eLife.75753 UR - https://doi.org/10.7554/eLife.75753 AB - Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture. KW - inflammation KW - inflammasome KW - gasdermin KW - bone KW - fracture KW - osteoclast JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -