Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling

Abstract

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.

Single-Dose Radial Extracorporeal Shock Wave Therapy Modulates Inflammation During Meniscal Tear Healing in the Avascular Zone

“…36 Additionally, the essential role of IL-1β in promoting bone healing after fracture has been confirmed. 35 These findings suggest a complex role for IL-1β in maintaining inflammation and promoting tissue regeneration.…”

Identification of a Biallelic Missense Variant in Gasdermin D (c.823G > C, p.Asp275His) in a Patient of Atypical Gorham‐Stout Disease in a Consanguineous Family

“…When we started to search for literature information about pyroptotic cell death and GSDMD, we could not obtain enough information about its possible influence on the skeletal system. However, later, we noted that one research group had started to focus on GSDMD as a contributing factor to bone remodeling and inflammatory bone loss, [ 20 , 23 ] and this was followed by another very important study from a different group that indicated a novel cell‐autonomous function of GSDMD by caspase‐8 cleavage in the osteoclasts. [ 22 ] The authors showed that the cleavage at Asp88 in addition to Asp275 leads to the accumulation of the shorter N‐terminal p20 fragment in the cytosol, resulting in suppression of the enhanced activation of osteoclasts by RANK signaling.…”

Chemotherapy activates inflammasomes to cause inflammation-associated bone loss

“…Briefly, nonadherent cells were removed by vigorous washes with PBS, and adherent BMMs were detached with trypsin-EDTA and cultured in culture media containing a 1:10 dilution of CMG for various experiments. Murine primary neutrophils were isolated by collecting bone marrow cells and subsequently over a discontinuous Percoll (Sigma-Aldrich, MO, USA) gradient as described previously ( Sun et al, 2022 ). Briefly, all bone marrow cells from femurs and tibias were washed by PBS and then resuspended in 2 ml PBS.…”