Pyroptosis in Periprosthetic Osteolysis

Abstract

Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation.

Keywords: NLRP3; aseptic loosening; inflammation; periprosthetic osteolysis; pyroptosis.

Figure 1

Pyroptosis in macrophages or osteoclasts. The NLRP3 inflammasome activates caspase-1, which activates GSDMD, the precursor of Pro-IL-1β and Pro-IL-18, respectively. Subsequent oligomerization of GSDMD-NT forms transmembrane pores in the plasma membrane, resulting in the release of IL-1β and IL-18. Melatonin increases butyrate content by affecting gut microbiota, which inhibits NLRP3 activation by binding to the GPR109A receptor. Both propionate and butyrate attenuate NLRP3 activation by inhibiting ASC assembly, but propionate is GPCRs-independent and HDAC-independent. BHB alleviates NLRP3 activation by inhibiting HDAC. TI particle stimulation up-regulates the expression levels of lncRNA Neat1 as well as BTK, aggravates the inflammatory response through the NF-κB pathway. Compound 17, a small molecule compound can rescue inflammatory osteolysis by inhibiting PTEN ubiquitination. PTEN inhibits the activation of NLRP3 and osteoclast activation by nuclear translocation of NF-κB p65. However, RANKL and LPS results in the ubiquitination of PTEN. BHB: β-hydroxybutyrate. BMDMs: bone marrow-derived macrophages. BTK: Bruton tyrosine kinase. Compound 17: a small molecule compound. GPCRs: G protein-coupled receptors. HDAC: histone deacetylase. lncRNA: long noncoding RNA. PTEN: phosphatase and tensin homolog. TI: titanium. UD: ubiquitination degradation.

Figure 2

TCP-mediated pyroptosis of calvarial osteocytes. TCP up-regulates the levels of ROS and MDA in osteocytes, as well as the activation of NLRP3-mediated osteocytes pyroptosis. In addition, the concentrations of IL-1β and LDH in serum increases. These effects can be reversed by the caspase-1 inhibitor VX765 or the NLRP3 inhibitor MCC950 or the ROS scavenger NAC. TCP: tricalcium phosphate. ROS: reactive oxygen species. MDA: malonaldehyde. Nrf2: antioxidant enzyme nuclear factor E2-related factor 2. LDH: lactate dehydrogenase. NAC: N-acetylcysteine.